Abstract Background Patients with lung cancer brain metastases can benefit from immune checkpoint inhibitors (ICI). However, intracranial responses are often limited and not always concordant with activity seen in extracranial disease. Defects in IFNγ signaling and HLA class-I antigen presentation machinery (APM) on malignant cells can drive immune evasion and ICI resistance, and have traditionally been viewed as interdependent. The possible role of these alterations in non-small cell lung cancer (NSCLC) brain progression remains poorly understood. Methods Using multiplex quantitative immunofluorescence, we measured and spatially mapped IFNγ signaling markers (pSTAT1 and IRF1) and multiple HLA class-I APM components (β2M, PSMB8, PSMB9, PSMB10, TAP1, TAP2, Tapasin, Calreticulin, and ERp57) in cancer cells and neighboring non-malignant stromal cells from two patient cohorts, including primary tumors, intra- and extra-cranial NSCLC metastases. We also studied tumor-infiltrating lymphocyte (TILs) subpopulations in the cohorts, performed whole transcriptomic analysis of parental human NSCLC H2030 cells and their brain metastatic counterpart H2030-BrM3, and expanded the results using spatial transcriptomics of human tumors. Results We found comparable levels of IFNγ signaling markers in primary and metastatic lesions and marked downregulation of multiple APM components in metastases, some of which were restricted to the brain. Downregulation of HLA class-I APM components was associated with reduced effector TILs and worse survival. Analysis of human parental H2030 and brain metastatic H2030-BrM3 lung adenocarcinoma cells showed comparable signaling responses after IFNγ stimulation and reduced HLA class-I APM markers in metastatic cells. Transcriptomic analysis of primary/metastatic cells and human tumors identified differential expression of multiple genes associated with HLA class-I APM downregulation. Conclusions Our results reveal that APM downregulation is a prominent feature of NSCLC brain metastases, is independent from local IFNγ signaling defects and is associated with unfavorable clinical features. We also identified candidate modulators of the APM pathway in brain metastases with potential translational significance.

Resistance to both naturally occurring anti-cancer immunity and to immunotherapy is common in patients with aggressive non-small cell lung cancer (NSCLC). Recent studies indicate a role of loss of the HLA class-I antigen presentation machinery (APM) protein β-2-microglobulin in acquired resistance to immune checkpoint blockers. However, the mechanisms, functional consequences and therapeutic potential of APM defects in NSCLC remain poorly understood. Using multiplexed immunofluorescence, we spatially mapped CD8+ effector Tumor-Infiltrating Lymphocytes (TILs) and the APM components TAP1 and TAP2 in 819 baseline/pre-treatment NSCLCs from patients treated with and without PD-1 axis blockers in 4 independent cohorts. The impact of TAP1/2 silencing in lung cancer cells using siRNAs and CRISPR/Cas9 was studied using transcriptomic analysis, phosphoprotein arrays, ATAC-sequencing, measurement of surface HLA-peptide complexes and in vitro tumor-antigen specific T-cell killing. We established autologous co-cultures of tumor and immune cells from primary human NSCLCs to study the functional impact of IL4Rα and/or PD-1 blockade using monoclonal antibodies. A high-throughput drug screen supported the identification of compounds able to increase TAP2 expression in NSCLC cells. We identified cancer cell selective TAP2 protein downregulation in 42.4

Lung cancer is the leading cause of cancer mortality among people with HIV (PWH), with increased incidence and poor outcomes. This study explored whether the tumor microenvironment (TME) of HIV-associated non-small cell lung cancer (NSCLC) limits tumor-specific immune responses. With a matched cohort of NSCLC samples from PWH and from people without HIV (PWOH), we used imaging mass cytometry, a linear mixed-effects model, and an artificial intelligence-based (AI-based) PageRank mathematical algorithm based on spectral graph theory to demonstrate that HIV-associated tumors have differential distribution of tumor-infiltrating CD8+ and CD4+ T cells, enriched for the expression of programmed cell death 1 (PD-1) and lymphocyte-activating gene 3 (LAG3), as well as activation and proliferation markers. We also demonstrate higher expression of immunoregulatory molecules (PD-L1, PD-L2, B7-H3, B7-H4, IDO1, and VISTA) among tumor-associated macrophages. Discrimination of cells between tumors from PWH versus those from PWOH was confirmed by spectral graph theory with 84.6% accuracy. Furthermore, we noted differences in spatial orientation of immune cells within the TME of PWH compared with PWOH. Additionally, cells from PWH, compared with those from PWOH, exhibited decreased tumor killing when exposed to HLA-matched NSCLC cell lines. In conclusion, our study demonstrates that the HIV-associated TME sustained a unique immune landscape, showing evidence of immune cells with enhanced immunoregulatory phenotypes and impaired antitumor responses, with implications for responses to immune checkpoint blocker therapies.

Proteases are essential enzymes that regulate numerous physiological processes and cellular signaling networks to maintain homeostasis and cellular fate. This regulation is mediated by a group of proteases with the primary function of cleaving peptide bonds, thereby modulating the activity of proteins for vital functions and influencing various cellular and physiological functions including digestion, absorption, cellular signaling, apoptosis, inflammation, immune response, cell growth, differentiation, cell death, and reproduction. Proteases define the fate of cells by modulating the downstream signal transduction pathways for modalities of cell death known as apoptosis, necroptosis, pyroptosis, and autophagy. Similarly, during inflammatory stimulation, proteases orchestrate a cascade of pathways that optimize the immune response to pathogens. Proteases play a crucial role in the pathogenesis of various human diseases, including cancer, metabolic, inflammatory, and neurological disorders. The activation of specific proteases determines the outcomes of different forms of cell death inflammation and imbalance may cause various pathological manifestations highlighted in this review. Understanding protease-mediated signaling mechanisms is therefore vital for elucidating disease pathogenesis and identifying potential therapeutic targets.

Proteases are hallmarks of various physiological processes and cellular signaling net-works that maintain homeostasis and cellular fate. This regulation is particularly medi-ated by carboxypeptidases, cysteine proteases, and metalloproteases, which function by cleaving peptide bonds, thereby modulating the activity of proteins and influencing their functional outcomes. Proteases play a regulatory role in various cellular processes, in-cluding cell growth, differentiation, cell death, immunity, and inflammation. Protease signaling influences the terminal outcomes of several forms of cell death, including apop-tosis, necroptosis, pyroptosis, and autophagy. Similarly, during inflammatory stimula-tion, proteases orchestrate a cascade of pathways that optimize the immune response to pathogens. Proteases are significant contributors to the development of various human diseases, including cancer, neurological disorders, and inflammatory disorders. The acti-vation of specific proteases determines the outcomes of different forms of cell death high-lighted in this review. Proteases are therefore critical targets for exploring future research on modulating their activity in various diseases and therapeutic targets. This review high-lights the important functions of protease family members in managing different aspects related to cellular balance and disease conditions.

e14014 Background: Although ~30% of patients with lung cancer brain metastasis (LBM) achieve intracranial response with immune checkpoint inhibitors (ICI), most have primary resistance, and those who initially respond develop rapid disease progression. The biological factors contributing to this unfavorable clinical scenario are poorly understood and could include distinct immunologic properties of tumors colonizing the brain. Using annotated tumor/patient cohorts, spatially resolved protein analysis, and in vitro models, we investigated the role of HLA class-I APM defects and interferon (IFN)-γ pathway in LBM. Methods: Using multiplex quantitative immunofluorescence, we measured the levels and spatial distribution of HLA class-I APM markers (β2M, tapasin, calreticulin, ERp57, TAP1, and TAP2), IFN-γ signaling (pSTAT1 and IRF-1), and tumor-infiltrating lymphocytes (TILs) (CD8, CD4, and FOXP3) in 56 LBM, 41 primary lung tumors (PLT), and 10 lung-extracranial metastases (ECM) represented in tissue microarrays. A subset of paired LBM/PLT samples from the same patients were also included (n=8). The spatial analysis of the markers was conducted using fluorescence co-localization and single-cell segmentation strategies. Associations between the markers, clinicopathological characteristics, and survival were studied. Protein expression of β2M and IFN-γ-sensitive markers (total STAT1, pSTAT1, IRF1, and PD-L1) before and after treatment with human recombinant IFN-γ was assessed using Western blot in cultured primary lung H2030 adenocarcinoma cells and their in vivo selected brain metastatic counterpart H2030-BrM3. Results: LBM showed significantly lower β2M, TAP2, and tapasin protein levels than PLT. However, LBM also showed higher expression of pSTAT1 and comparable levels of IRF-1 relative to PLT. Similar results were seen in paired LBM/PLT samples, but not in ECM samples. Tumors with low β2M showed reduced CD8+, CD4+, and FOXP3+ TILs. In LBM no significant association between β2M and IFN-γ pathway markers or major clinicopathologic and molecular patient/tumor features were found. LBM samples from patients progressing after radiotherapy and/or chemotherapy showed significantly lower β2M levels. Reduced β2M expression was associated with shorter overall survival in PLT but not in LBM. The brain metastatic H2030-BrM3 cell line showed lower β2M expression both at baseline and after IFN-γ treatment compared with their parental H2030 counterpart. Conclusions: HLA class-I APM downregulation is a prominent feature of LBM, is independent of local adaptive/inducible IFN-γ stimulation, and is associated with unfavorable clinical features. These findings support that HLA class-I APM deficiency plays a major role in immune evasion and immunotherapy resistance in patients with LBM.

Fas-associated death domain (FADD) is an adaptor protein that predominantly transduces the apoptosis signal from the death receptor (DR) to activate caspases, leading to the initiation of apoptotic signaling and the coordinated removal of damaged, infected, or unwanted cells. In addition to its apoptotic functions, FADD is involved in signaling pathways related to autophagy, cell proliferation, necroptosis, and cellular senescence, indicating its versatile role in cell survival and proliferation. The subcellular localization and intracellular expression of FADD play a crucial role in determining its functional outcomes, thereby highlighting the importance of spatiotemporal mechanisms and regulation. Furthermore, FADD has emerged as a key regulator of inflammatory signaling, contributing to immune responses and cellular homeostasis. This review provides a comprehensive summary and analysis of the cellular dynamics of FADD in regulating programmed cell death and inflammation through distinct molecular mechanisms associated with various signaling pathways.

Abstract Among people with HIV (PWH), non-small cell lung cancer (NSCLC) is increasing in incidence, presents with more advanced disease, and portends a worse prognosis compared to the general NSCLC population. Despite effective control of viral replication with antiretroviral therapy (ART), PWH have evidence of immune dysfunction, and it is unknown whether these immune perturbations impact the tumor microenvironment (TME) to influence disease disparities.Here we preclinically model HIV-associated NSCLC using MISTRG6-A2, a humanized mouse system that is highly optimized for development of functional innate and adaptive immune cells. We compare tumor growth and immune features of HIV-infected, ART-suppressed MISTRG6-A2 hosts to uninfected hosts, with parameters informed by parallel analyses of human tissue samples obtained from PWH with NSCLC, and non-HIV controls.MISTRG6-A2 mice were engrafted with human CD34+ HSPCs from HLA-A*02-expressing donors on post-natal day 2 and intravenously infected with HIV-1 at 6 weeks of age. When HIV viral titers were >106 copies of viral RNA/ml plasma and hCD4 T cells were depleted, ART was initiated (RAL/FTC/TDF). When plasma viral RNA was undetectable and CD4 T cells recovered, NSCLC PDX tissue from HLA-A*02-expressing tumor was implanted into these HIV-infected, ART-suppressed MISTRG6-A2 mice as well as non-infected littermate controls which had received HSPCs from the same donor. HIV-infected mice displayed enhanced growth of PDX tissue (mean tumor size 206.7 mm3 vs 110.2 mm3; p < 0.05).Quantitative immunofluorescence of the TME from these hosts revealed significantly increased infiltration of CD4 and CD8 T cells in tumors of HIV-NSCLC mice (p<0.01 and 0.05, respectively); of note, enhanced T cell infiltration was restricted to tumors, with similar frequency of CD4 and CD8 T cells detected in spleen, lung and liver tissues of HIV-infected vs uninfected hosts. Staining of tumor epitopes revealed increased expression of B2M and EGFR in tumors from HIV-NSCLC mice (mean qIF scores in NSCLC vs HIV-NSCLC 3.8 × 106 vs 1.2 × 107 for B2M, p<0.001; 440 vs 1,971 for EGFR, p<0.01), consistent with our findings in samples from HIV-NSCLC tumor tissues vs NSCLC tumor tissues. Of note, elevated EGFR staining was only present in tumor tissue, not found in stromal cells or other tissues. Single cell transcriptomic analyses of the TME revealed prominent interferon and antigen presentation signatures in HIV-NSCLC tumors, as well as differential expression of immunoregulatory molecules.These results demonstrate the fidelity of the HIV-NSCLC MISTRG6-A2 system as a model for HIV-associated NSCLC and suggest EGFR-directed therapies as potentially relevant in this neglected disease. Citation Format: Melani Juric, Gabriel Kaufmann, Li Zhu, Kishu Ranjan, Kriti Agrawal, Barani Kumar Rajendran, Jyothi K. Rajashekar, Hongyu Zhao, Yuval Kluger, Brinda Emu, Kurt A. Schalper, Priti Kumar, Richard A. Flavell, Michael Chiorazzi. A novel humanized mouse model recapitulates the unique TME found in patients with HIV-associated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 101.

Endocytosis in mammalian cells is a fundamental cellular machinery that regulates vital physiological processes, such as the absorption of metabolites, release of neurotransmitters, uptake of hormone cellular defense, and delivery of biomolecules across the plasma membrane. A remarkable characteristic of the endocytic machinery is the sequential assembly of the complex proteins at the plasma membrane, followed by internalization and fusion of various biomolecules to different cellular compartments. In all eukaryotic cells, functional characterization of endocytic pathways is based on dynamics of the protein complex and signal transduction modules. To coordinate the assembly and functions of the numerous parts of the endocytic machinery, the endocytic proteins interact significantly within and between the modules. Clathrin-dependent and -independent endocytosis, caveolar pathway, and receptor mediated endocytosis have been attributed to a greater variety of physiological and pathophysiological roles such as, autophagy, metabolism, cell division, apoptosis, cellular defense, and intestinal permeabilization. Notably, any defect or alteration in the endocytic machinery results in the development of pathological consequences associated with human diseases such as cancer, cardiovascular diseases, neurological diseases, and inflammatory diseases. In this review, an in-depth endeavor has been made to illustrate the process of endocytosis, and associated mechanisms describing pathological manifestation associated with dysregulated endocytosis machinery.

2623 Background: Determinants of sensitivity and resistance to immune checkpoint inhibitors (ICIs) are poorly understood. An intact HLA class-I antigen presentation machinery (APM) is necessary for tumor-antigen recognition by effector T-cells and disruptions to the APM can cause ICI resistance. The peptide loading complex (PLC) is a multi-chaperone complex located in the endoplasmic reticulum in which tapasin (Tap), calreticulin (CalR) and ERp57 play major roles. The PLC allows for optimal peptide selection and loading onto HLA class-I heavy chain and is critical for adequate cell surface presentation of peptide-HLA complexes. We studied the frequency and clinical significance of cancer-cell selective PLC protein defects in human NSCLC. Methods: Multiplex quantitative immunofluorescence (mQIF) was performed to simultaneously and spatially measure cytokeratin (CK), Tap, CalR, ERp57 and CD8 protein levels in 1,031 primary NSCLCs from 5 independent cohorts represented in tissue microarrays. The protein levels were measured in CK-positive cancer-cells and in CK-negative stromal cells. The presence of lower marker levels in malignant cells relative to stromal cells within the same sample was considered as cancer-cell selective downregulation. Cohorts #1-3 included baseline samples from patients treated without ICIs and Cohort #4 included samples from patients treated with ICIs. Cohort #5 contained lung adenocarcinomas clinically tested for EGFR and KRAS mutations. The association between the levels of Tap, CalR and ERp57, their association with clinicopathologic variables, CD8+ T-cell levels and outcomes were studied. Results: mQIF analysis identified cancer-cell selective downregulation of Tap, CalR and/or ERp57 in 73%, 81%, 68% and 75% of cases from Cohorts #1-4, respectively. The most common PLC alterations were cancer-cell downregulation of Tap alone in Cohorts #1 (32%), #3 (34%) and #4 (36%); and Tap-CalR in Cohort #2 (29%). Tap and ERp57 levels were significantly higher in stage IV than in earlier stage tumors. The PLC marker levels and the frequency of cancer-cell selective downregulation were comparable across EGFR and KRAS mutated samples. NSCLCs with cancer-cell Tap downregulation had lower CD8+ T-cell infiltration and shorter OS across all cohorts that reached statistical significance in Cohort #4 (median OS 12.08 vs 21.00, HR=1.72, 95% CI 1.02-2.89, p=0.034). The cancer-cell selective downregulation of CalR was associated with shorter OS in cohorts #1 and #3. Conclusions: HLA class-I PLC components show variable levels in treatment naïve NSCLCs. Downregulation of Tap in cancer-cells, alone or in combination with other PLC members occurs in up to 60% of cases and is associated with reduced CD8+ TILs and shorter OS preferentially in patients treated with ICIs. Cancer-cell Tap downregulation could mediate primary ICI resistance and has biomarker potential.

The Fas associated Death Domain (FADD) is an adaptor protein that predominantly transduces apoptosis signal from death receptor (DR) to activate caspases, leading to the initiation of apoptotic signaling and the coordinated removal of damaged, infected, or unwanted cells. In addition to its apoptotic functions, FADD is involved in signaling pathways related to autophagy, cell proliferation, necroptosis, and cellular senescence, indicating its versatile role in cell survival and proliferation. The subcellular localization and intracellular expression of FADD play a crucial role in determining its functional outcomes, thereby highlighting the importance of spatiotemporal mechanisms and regulation. Furthermore, FADD has emerged as a key regulator in inflammatory signaling, contributing to immune responses and cellular homeostasis. This review provides a comprehensive summary and analysis of cellular dynamics of FADD in regulating of programmed cell death and inflammation through distinct molecular mechanisms associated with various signaling pathways.

Most essential pattern-recognition receptors regulating innate immune functions are toll-like receptors (TLRs). TLRs are characterized by lack of concurrent epithelial markers and are typically identified by their gene expressions. One major mechanism by which TLRs generate their effector functions is by triggering inflammatory responses. Activation of TLRs can impact initiation, advancement, and control of cancers by regulating the inflammatory microenvironment. Several TLRs have been implicated in human cancers and some of them are identified as cancer biomarkers as well; for example, TLRs 2, 3, 5 are expressed more frequently in most cancers. Knowing the upregulation and downregulation of the TLR genes in human cancers will be useful for the development of newer therapeutic targets which can disrupt the pathways associated with such deregulation. We present here the various TLRs and their functions in human lung, gastric, breast, prostate, oral, ovarian, colorectal, cervical, esophageal, bladder and hepatic cancers.

Background Among people with HIV (PWH), lung cancer is the leader cause of cancer mortality, with increased risk and poor clinical outcomes compared to people without HIV (PWOH). HIV is known to result in persistent global immune dysfunction despite antiretroviral therapy, but little is known about the lung cancer tumor microenvironment. This study explored whether the tumor microenvironment (TME) of HIV-associated non-small cell lung cancer (NSCLC) is associated with an immunoregulator environment that limits tumor-specific immune responses. Methods A tissue microarray was constructed with NSCLC tumors from 18 PWH and 19 PWOH (matched for histological subtype, stage, year of diagnosis, age, sex and smoking status), and incubated with metal-conjugated antibodies for evaluation by imaging mass cytometry (IMC). IMC marker scores were extracted by automated cell segmentation and single-cell data was analyzed by Phenograph using unsupervised cell-segmentation and clustering of cells. Evaluation of tumor infiltrating immune cells, CD4+ and CD8+ T cells as well as CD68+ tumor associated macrophages were characterized for marker expression using a linear mixed-effects model. Additionally, a computational strategy based on the PageRank mathematical algorithm was used in order to establish an unsupervised and cell segmentation-independent signature associated with HIV status to discriminate differential expression of immune cell markers within the TME of the two groups. Peripheral blood mononuclear cells (PBMCs) from HLA-A02 donors (PWH and PWOH) were co-incubated with HLA-A02 lung cancer cell lines to quantify tumor killing (by Annexin V staining) and expression of T cell markers Lag-3 and CD25. Results Within the TME from HIV+ tumors, there is comparable level of infiltration of lymphocytes and tumor associated macrophages (TAMs) compared to non-HIV tumors, with a trend towards increased CD8+ T cells and decreased CD4:CD8 ratio among HIV+ tumors. Using a random effects model of individual markers, HIV+ tumors revealed increased expression of Ki67 and Granzyme B (GRZB) among CD8+ T cells; increased Ki67 and PD-1 among CD4+ T cells; and increased PD-L1, PD-L2, and Ki67 among TAMS. Unsupervised clustering analysis from IMC data demonstrated differential distribution of tumor infiltrating CD8+ T cell clusters between HIV+ and non-HIV tumors, defined by marker expression patterns. Three clusters were significantly elevated in HIV+ tumors (57.1% vs. 21.7% in non-HIV tumors, p<0.0001). All three clusters had comparatively elevated PD-1 and Lag-3 expression with varying expression of activation and proliferation markers CD25 and Ki67. Within tumor-infiltrating CD4+ T cells, a cluster characterized by checkpoint protein expression (PD-1+ and LAG-3) was also highly represented in HIV+ cases (35.2% vs. 9.8% in non-HIV cases, p<0.0001). HIV+ tumor-associated macrophages (TAM) had higher expression of immunoregulatory molecules (PD-L1, PD-L2, B7-H3, B7-H4, IDO1 and VISTA), confirmed by the expansion of three clusters comprising 58.8% of TAMs vs. 17.8% in non-HIV tumors (p<0.0001). Discrimination of cells between HIV+ and HIV-TME was further confirmed by spectral graph theory with 84.6% accuracy, with a combination of markers on TAMs and T cells. Lastly, PBMCs from PWH exhibited decreased tumor killing when exposed to HLA-matched NSCLC cell lines compared to PBMCs from PWOH. CD8+ T cells from PWH additionally had increased expression of immune checkpoint inhibitor Lag-3 upon exposure to tumor cells. Conclusions Our study demonstrates that the TME of HIV+ patients is characterized by a unique immune landscape, distinct from that of PWOH, with evidence of expansion of immune cells with enhanced immunoregulatory phenotypes and associated with impaired anti-tumor responses.

Introduction: Lung cancer is the leading cause of cancer-related death among PWH with a relative risk that is over 3-fold higher compared to the uninfected population. In addition, HIV-infected patients with non-small cell lung cancer (NSCLC) have a significantly worse prognosis. The determinants for these associations remain uncertain. Methods: We investigated the immune contexture of 18 primary NSCLCs from PWH and 19 clinicopathologically matched NSCLCs from HIV-negative cases represented in tissue microarrays using 37-plex Imaging Mass Cytometry (IMC) panels including cell phenotype markers (CK,CD4,CD8,CD20,CD45RO,CD25,etc), immunomodulatory targets (PD-L1,PD-L2,B7-H3,B7-H4,B2M,etc) and DNA damage response/repair (DDR) indicators (γH2AX, RAD51,BRCA1,53BP1,etc). The samples were analyzed using single-cell tissue segmentation and spatial analysis. A subset of cases was also studied using whole exome DNA sequencing (WES) and mRNA sequencing (RNAseq). Results: NSCLCs from PWH showed comparable levels of tumor infiltrating lymphocytes (TILs) relative to HIV-negative cases with a trend towards a lower CD4+/CD8+ cell ratio. However, CD4+ and CD8+ TILs in PWH showed higher levels of markers associated with T-cell activation and dysfunction including GZB, CD25, Ki-67, PD-1, LAG-3, and TIM-3 than non-HIV tumors. The epithelial tumor cells in HIV-associated cases showed higher levels of the immunomodulatory ligands PD-L1, CD47, B7-H4 and VISTA; and altered levels of the DDR markers γH2AX, BRCA1 and 53BP1 relative to the non-HIV controls. Differences were also seen in tumor-associated macrophages consistent with an immune regulatory environment. The spatial analysis of tumor and immune cells revealed a distinct topographic distribution of these cells in HIV-associated malignancies. WES analysis showed a higher nonsynonymous tumor mutational burden in HIV-associated tumors (400 vs 202 mean mutations/exome) with increased predicted HLA class-I neoantigens and a numerically higher immunoediting score than the non-HIV group. Exploratory analysis identified enrichment in RYR2 and KIAA1671 gene mutations in HIV-associated malignancies. RNAseq revealed distinct mRNA expression profiles of HIV-positive and negative NSCLCs with a fraction of transcripts showing differential expression associated with tumor suppressor functions, interleukin signaling and DDR. Conclusion: NSCLCs in PWH display profound immunological and genomic alterations suggesting defective immunosurveillance. Our study reveals novel characteristics of HIV-associated NSCLC with possible clinical implications for this growing and understudied population. Citation Format: Shruti Desai, Kishu Ranjan, Syim Salahuddin, Ramsey Yusuf, Jianlei Gu, Daiwei Tang, Yong Kong, Barani Kumar Rajendran, Hongyu Zhao, Yuval Kluger, Sarah Goldberg, Brinda Emu, Kurt Alex Schalper. Tumor immune microenvironment &genomic features of non-small cell lung carcinomas in patients with HIV (PWH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6762.

AbstractEndeavors to identify potentially protective variables for COVID‐19 impact on certain populations have remained a priority. Multiple attempts have been made to attribute the reduced COVID‐19 impact on populations to their Bacillus–Calmette–Guérin (BCG) vaccination coverage ignoring the fact that the effect of childhood BCG vaccination wanes within 5 years while most of the COVID‐19 cases and deaths have occurred in aged with comorbidities. Since the supposed protection being investigated could come from heterologous ‘trained immunity’ (TI) conferred by exposure to Mycobacterium spp. (i.e., environmental and BCG), it is argued that the estimates of the prevalence of TI in populations currently available as latent tuberculosis infection (LTBI) prevalence would be a better variable to evaluate such assertions. Indeed, when we analyze the European populations (24), and erstwhile East and West Germany populations completely disregarding their BCG vaccination coverage, the populations with higher TI prevalence consistently display reduced COVID‐19 impact as compared to their lower TI prevalence neighbors. The TI estimates of the populations not the BCG coverage per se, negatively correlated with pandemic phase‐matched COVID‐19 incidences (r(24): −0.79 to −0.57; p‐value < .004), mortality (r(24): −0.63 to −0.45; p‐value < .03), and interim case fatality rates (i‐CFR) data. To decisively arrive at dependable conclusions about the potential protective benefit gained from BCG vaccination in COVID‐19, the ongoing or planned randomized controlled trials should consciously consider including measures of TI as: (a) all individuals immunized do not respond equally, (b) small study groups from higher background TI could fail to indicate any protective effect.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.