CD4+ T helper (Th) cells contribute to tumor immunity, yet the subsets and differentiation programs involved remain unclear. Here, we show that the transcription factor Eomesodermin (Eomes) is essential for Th-mediated anti-tumor immunity. Eomes orchestrated the differentiation and maintenance of an exhausted-like Th cell lineage, transcriptionally and functionally distinct from conventional effector or memory Th subsets. This Eomes-dependent program was enhanced by 4-1BB stimulation and promoted effective Th-cell-mediated tumor control. The progenitor subset of this lineage (pTh) expressed stemness-associated transcription factors, displayed self-renewal capacity, and seeded effector subsets capable of controlling tumor growth. At the transcriptional level, Eomes supported the survival, metabolic fitness, and apoptotic resistance of this lineage. Eomes⁺ pTh cells exhibited conserved transcriptional features in humans across multiple tumor types. As the most expanded Th cell population upon immune checkpoint inhibitor therapy, targeting these cells has potential to improve current immunotherapies.

Brain metastases are a common complication among patients with non-small cell lung cancer and are historically associated with significant morbidity and limited survival. Although surgery and radiation therapy remain essential pillars in the clinical management of brain metastases, the development of several pharmacologic agents with activity in the central nervous system has broadened the role of systemic therapies for treating brain metastases. There is accumulating evidence that, in the appropriate clinical scenarios, systemic therapies may be used to manage both intracranial and extracranial disease while delaying local therapy and mitigating potential treatment-related morbidity. Determining the optimal treatment approach requires careful consideration of the intracranial tumor burden, location of lesions, pathologic and molecular profile, local and systemic therapy options, and overall prognosis. This review will provide updates on the medical management of non-small cell lung cancer brain metastases, with a focus on recent advances in systemic therapy options.

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.

Background:Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) is approved for the treatment of advanced melanoma but is limited by the need for patients to undergo surgical tumor resection. Malignant pleural effusions (MPE) may represent a more accessible source of tumor-reactive T cells. Here, we characterize the cellular composition as well as the transcriptional and functional properties of T cells from MPE compared with pulmonary metastasis and blood from a patient with melanoma. Methods:The immune cellular composition was immunophenotyped by high-dimensional flow cytometry from synchronously collected MPE, a lung metastasis, and blood from a patient with metastatic melanoma. Sorted CD3+ T cells were profiled by single-cell RNA sequencing (scRNA-seq) and T cell receptor sequencing (scTCR-seq). TCR reactivity to autologous tumor was evaluated through in vitro activation assays with TCR-transduced Jurkat and autologous cancer cells. The killing capacity of ex vivo expanded T cells of autologous cancer cells was assessed through in vitro cytotoxicity assays. Results:MPE had higher proportions of CD45+ immune cells and CD3+ T cells (70.5% vs 50%) compared with tumor and was enriched for effector CD8+ T cells, CCR7C-D45RA- effector memory CD4+ T cells, and quiescent CD25highCD127low regulatory CD4+ T cells. MPE T cells exhibited lower levels of co-inhibitory receptors (PD-1, LAG-3, TIGIT, TIM-3) expression relative to tumor. ScRNA-seq showed enrichment of NK-like effector CD8+ T cells in MPE. Pseudotime analysis indicated that MPE T cells were less exhausted than tumor T cells. The clonal repertoire of MPE and tumor highly overlapped, including 62.2% of predicted neoantigen-specific (NeoTCR) clonotypes. Notably, clonally-related NeoTCR T cells in MPE exhibited higher cytotoxic and stemness, and lower exhaustion signatures compared with sister clones in the tumor. Two of four selected NeoTCR clonotypes transduced in Jurkat cells demonstrated MHC class I-restricted reactivity in co-culture with autologous cancer cells. MPE T cells also readily expanded in the presence of high-dose IL-2 and demonstrated MHC class I-dependent killing of autologous cancer cells. Conclusions:MPE harbors polyclonal, tumor-reactive T cells with lower features of terminal exhaustion and higher cytotoxic potential relative to tumor T cells. MPE may therefore serve as a more accessible source for TIL therapy.

Specialized immune cells that reside in tissues orchestrate diverse biological functions by communicating with parenchymal cells1. The contribution of the innate immune compartment in the meninges and the central nervous system (CNS) is well-characterized; however, whether cells of the adaptive immune system reside in the brain and are involved in maintaining homeostasis is unclear2-4. Here we show that the subfornical organ (SFO) of the brain is a nucleus for parenchymal αβ T cells in the steady-state brain in both mice and humans. Using unbiased transcriptomics, we show that these extravascular T cells in the brain are distinct from meningeal T cells: they secrete IFNγ robustly and express tissue-residence proteins such as CXCR6, which are required for their retention in the brain and for normal adaptive behaviour. These T cells are primed in the periphery by the microbiome, and traffic from the white adipose and gastrointestinal tissues to the brain. Once established, their numbers can be modulated by alterations to either the gut microbiota or the composition of adipose tissue. In summary, we find that CD4 T cells reside in the brain at steady state and are anatomically concentrated in the SFO in mice and humans; that they are transcriptionally and functionally distinct from meningeal T cells; and that they secrete IFNγ to maintain CNS homeostasis through homeostatic fat-brain and gut-brain axes.

While immune-modulating therapies which enhance antitumor T cell function have revolutionized cancer therapy, including for patients with brain metastases, the antigen specificity of intratumoral T cells remains poorly characterized. We performed droplet-based 5’ single-cell RNA sequencing and T cell receptor (TCR) sequencing to characterize the transcriptional profile and clonal repertoire of tumor-infiltrating T cells in resected tumors from patients with previously untreated non-small cell lung cancer (NSCLC) brain metastases (n=6). We identified a population of clonally-expanded, CXCL13+CD8+ T cells enriched for transcriptional signatures predictive of tumor reactivity. Using a high-throughput T cell antigen identification method developed by our group, we screened 164 TCRs from clonally-expanded and/or CXCL13+CD8+ T cells against 2,289 putative neoantigens in addition to 146 tumor-associated antigens. In total, we identified reactivities for 21% (n=35) of the TCRs screened. Consistent with recent studies, we observed that the transcriptional state of the T cell was more predictive of tumor reactivity than the degree of clonal expansion. Of TCR specificities identified, 25.7% (n=9) of TCRs were reactive to neoantigens derived from somatic single-nucleotide variants specific to each patient (private antigen). Intriguingly, 54.3% (n=19) of the TCRs were reactive to unmutated peptides expressed by many patients’ lung tumors (public antigens). In summary, we present a deep characterization of the antigenic reactivities of intratumoral T cells in NSCLC brain metastases. Our data are consistent with an emerging body of literature that has theorized that “missing reactivities” from neoantigen-centric studies arise from complex mechanisms of genetic and epigenetic dysregulation within tumors. Further characterization of these “public antigens” may provide the basis for novel antigen-directed T cell therapies.

In 2022, the American Council for Graduate Medical Education (ACGME) recommended that core faculty (CF) in medical subspecialty fellowships receive at least 0.1 full-time equivalent (FTE) salary support, with plans to enforce compliance in July 2023. After early feedback raised concerns about potential unintended consequences, ACGME deferred enforcement to July 2024. Hence, there is an urgent need to understand the ramifications of providing FTE support for CF. In 2020, the Yale hematology and medical oncology (HO) fellowship program began providing 0.1 FTE support to all CF. Perceptions regarding this were assessed via surveys distributed to all CF in 2021 and 2022 and to all HO fellows in 2021. The vast majority (83.3%) of CF survey respondents reported improved job satisfaction and an increased sense of involvement in the fellowship program as a result of the new 0.1 FTE-supported CF program. Most CF increased attendance at fellowship conferences, devoted more time to mentorship, and increased participation in recruitment. In free text comments, CF respondents described that providing 0.1 FTE support made them “feel rewarded,” gave them “a sense of commitment” to the fellowship, and helped “offset clinical requirements.” HO fellows reported “a positive impact” of the new program with faculty being “more present at lectures.” The median number of times faculty were available to interview fellowship applicants rose markedly after introduction of the program. The FTE-supported CF program was viewed enthusiastically by fellows and faculty, resulting in increased CF involvement in fellowship education and recruitment.

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.

INTRODUCTION: Radiation necrosis (RN), a common and morbid side effect of radiosurgical treatment of brain metastasis, is becoming more prevalent as immunotherapy options and patient survival improve. Thought to be immunologically driven, the pathophysiology of RN remains poorly defined. Further, RN is often indistinguishable from regrowing metastases after stereotactic radiosurgery (SRS), requiring invasive brain biopsy for diagnosis. METHODS: We collected 20 intraoperative samples from patients undergoing craniotomy for RN and/or metastatic tumor, as well as time-matched blood and CSF. We created a tissue bank, processed samples, and using fluorescence-activated cell sorting (FACS) and 10x Genomics single cell RNA sequencing, analyzed the cellular immune profile of lesional tissue, blood, and CSF. RESULTS: RN tissue demonstrates a robust, detectable expression of immune cells, including CD8+ and CD4+ T cells, natural killer (NK) and myeloid cells. Importantly, clustering of RN-derived immune cells (including T cells, myeloid cells, and NK cells) is reflected in the blood and CSF, with similar immune profiles. We demonstrate a subpopulation of myeloid cells with a microglia signature (CD14+, LYZ-, MS4A7+), and a separate population expressing interferon-stimulated gene (ISG). Supporting these findings, pathway analysis of top blood markers reveals pathways involved in innate and inflammatory immune responses in the blood of RN patients. CONCLUSIONS: These findings demonstrate the feasibility of extracting live cells from RN tissue for scRNAseq analysis and suggest that there are unique signatures of RN that can be detected in the blood and CSF of patients. This work has the potential to open new avenues for improved diagnostic and therapeutic approaches to allow earlier detection and more effective treatment of RN in patients with metastatic brain tumors.

The cytokine IL-18 has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18's anticancer efficacy. A decoy-resistant form of IL-18 (DR-18) that avoids sequestration by IL-18BP while maintaining its immunostimulatory potential has recently been developed. Here, we investigated the therapeutic potential of DR-18 in renal cell carcinoma (RCC). Using pantumor transcriptomic data, we found that clear cell RCC had among the highest expression of IL-18 receptor subunits and IL18BP of tumor types in the database. In samples from patients with RCC treated with immune checkpoint inhibitors, IL-18BP protein expression increased in the tumor microenvironment and in circulation within plasma in nonresponding patients, and it decreased in the majority of responding patients. We used immunocompetent RCC murine models to assess the efficacy of DR-18 in combination with single- and dual-agent anti-PD-1 and anti-CTLA-4. In contrast to preclinical models of other tumor types, in RCC models, DR-18 enhanced the activity of anti-CTLA-4 but not anti-PD-1 treatment. This activity correlated with intratumoral enrichment and clonal expansion of effector CD8+ T cells, decreased Treg levels, and enrichment of proinflammatory antitumor myeloid cell populations. Our findings support further clinical investigation of the combination of DR-18 and anti-CTLA-4 in RCC.

Effective anti-tumor immunity is driven by cytotoxic CD8+ T cells with specificity for tumor antigens. However, the factors that control successful tumor rejection are not well understood. Here we identify a subpopulation of CD8+ T cells that are tumor-antigen-specific and can be identified by KIR expression but paradoxically impair anti-tumor immunity in patients with melanoma. These tumor-antigen-specific KIR+CD8+ regulatory T cells target other tumor-antigen-specific CD8+ T cells, can be detected in both the tumor and the blood, have a conserved transcriptional program and are associated with a poor overall survival. These findings broaden our understanding of the transcriptional and functional heterogeneity of human CD8+ T cells and implicate KIR+CD8+ regulatory T cells as a cellular mediator of immune evasion in human cancer. Tumor-antigen-specific CD8+ T cells are generally thought to help fight against cancer, but here the authors identify a subpopulation of CD8+ T cells that are associated with a poor clinical outcome in melanoma. Although these cells can recognize tumor antigens, they suppress cancer immunity.

Abstract While therapies enhancing antitumor T cell function have clinical efficacy for patients with brain metastases, patients with high-grade gliomas fail to benefit. How the brain tumor microenvironment differentially shapes T cell function remains unknown. We performed droplet-based single-cell RNA and T cell receptor sequencing on immune cells from tumor and blood of patients with newly diagnosed non-small cell lung cancer brain metastases (n=10) and high-grade glioma (n=12). In total, we examined 220,049 high-quality immune cells, including 159,043 T cells. Tumor-infiltrating T cells in metastases were more abundant (p=0.005), more clonally expanded (p=0.039), and had a less diverse clonal repertoire (p=0.033). While no differences were observed among CD8+ T cells, a population of CXCL13+CD4+ T cells was more abundant in metastases (6.03% vs. 1.82%, p=0.004). This population expressed genes encoding transcriptional factors (BCL6, MAF), co-inhibitory receptors (PDCD1, LAG3, TIGIT), and effector cytokines (IL21, IL4, IFNG) characteristic of follicular helper T cells though notably lacked expression for the canonical chemokine receptor CXCR5. CXCL13+CD4+ T cells were highly expanded, had minimal clonal overlap with other populations, largely confined to the tumor, associated with germinal center B cell and plasma cell signatures, and resembled T cell populations predictive of anti-PD-1 therapy response in extracranial disease. Based on the expression of potential ligand-receptors and downstream signaling targets, CXCL13+CD4+ T cells were predicted to interact with B cells and antigen-presenting cells, as seen in tertiary lymphoid structures. To investigate the relevance of CXCL13+CD4+ T cells in glioblastoma, we analyzed bulk RNA sequencing data from The Cancer Genome Atlas (n=160) and observed a trend towards longer overall survival in patients with high follicular helper-like expression. In summary, we identified a follicular helper-like CD4+ T cell population that is preferentially found in brain metastases and may be a feature of productive antitumor immune responses in human brain tumors.

Spatial omics technologies, including highly multiplexed histologic protein assays, nucleic acid abundance and/or sequence mapping, and spatial epigenetics assays, offer powerful tools for interrogating the complex biology of human tissues. These technologies have been broadly applied in basic and translational research, which presages deployment in clinical settings as well. In this article, we discuss spatial omics technologies with an emphasis on retrieval of disease-related information in single samples, with potential clinical applications in specialties such as oncology and immunology, and in the development of personalized treatment. Capable of localizing detailed molecular information within histologic structures, spatial omics technologies provide both cell-intrinsic information and microenvironmental interaction context. This will allow more precise diagnostic and prognostic classifications and more accurate predictions about treatment responses to be made. While technical and financial challenges to widespread deployment in clinical laboratories remain, spatial omics technologies are expected to dramatically expand actionable information obtained by human tissue sampling for pathologic analysis.

Abstract BACKGROUND Immune checkpoint inhibitors (ICI) can have activity in lung cancer brain metastases (LBM). However, the duration of responses is limited and most patients with LBM do not benefit from these therapies. Alterations in HLA class-I antigen presentation machinery via beta-2 microglobulin (B2M) downregulation and disruption of IFN-γ sensing were identified as mechanisms of immune evasion and ICI resistance in solid tumors. However, the expression and clinical significance of these pathways in LBM are poorly understood. METHODS Using multiplex quantitative immunofluorescence we measured the localized expression of B2M protein; and the IFN-γ pathway markers phospho-STAT1 (pSTAT1), and Interferon Regulatory Factor 1 (IRF-1) in 67 immunotherapy naïve LBM and 45 primary lung tumors (PLT), including 15 patients with paired samples represented in a tissue microarray. The markers were selectively measured in cytokeratin + tumor cells and in cytokeratin- stromal cells. Associations between the markers, PD-L1, TILs and clinicopathologic variables were compared between LBM and PLT. RESULTS LBM showed lower levels of B2M in both tumor and stroma compartments compared to PLT. In contrast, high tumor and stromal levels of pSTAT1 were observed in LBM and comparable levels of IRF-1 were found between both tumor sites. Consistently across LBM and PLT samples, pSTAT1 and IRF1 were strongly correlated, and a positive but weaker association was observed with B2M and TILs. Only in PLT high tumor-cell PD-L1 expression was associated with high levels of IRF-1. No statistically significant association was observed between the markers and clinicopathologic variables. Tumor B2M downregulation in PLT was associated with worse survival. CONCLUSION LBM show distinct immunomodulatory properties relative to PLT, characterized by reduced HLA class-I antigen presentation machinery, elevated IFN-γ signaling and reduced local adaptive immune responses. These results support differences in immune evasion mechanisms in LBM compared with the PLT, which may have biological and clinical implications.

The T cell receptor (TCR) endows T cells with antigen specificity and is central to nearly all aspects of T cell function. Each naïve T cell has a unique TCR sequence that is stably maintained during cell division. In this way, the TCR serves as a molecular barcode that tracks processes such as migration, differentiation, and proliferation of T cells. Recent technological advances have enabled sequencing of the TCR from single cells alongside deep molecular phenotypes on an unprecedented scale. In this review, we discuss strengths and limitations of TCR sequences as molecular barcodes and their application to study immune responses following Programmed Death-1 (PD-1) blockade in cancer. Additionally, we consider applications of TCR data beyond use as a barcode.

PURPOSE: Diversity, equity, and inclusion (DEI) are core principles in medical education and essential elements in eliminating health and workforce disparities. Over the past several years, institutional DEI initiatives have led to increases in the numbers of underrepresented trainees and faculty at Yale School of Medicine (YSM) and Yale Cancer Center (YCC). In 2021, the Yale Hematology/Oncology (HO) Fellowship Program created a DEI curriculum for Yale HO Fellows, designed by the HO Chief Fellows with guidance from Fellowship Program Leadership and the Vice Chair of DEI for YCC. The goals of the DEI curriculum were to foster a programmatic culture of inclusion and empower fellows to identify and respond to discrimination events in the workplace. METHODS: A baseline needs-based assessment was performed with online anonymized surveys. The six-question survey was designed to assess topic preferences and witnessed discrimination events; all HO fellows (n = 27) were emailed a link to the survey. Based on the needs assessment, a five part DEI curriculum was designed, which included 1) an interactive session with the Vice Chair of DEI, 2) a journal club with the Deputy Dean and Chief Diversity Officer at YSM, 3) an interactive session on advancing gender equity through allyship and awareness led by external consultants, 4) an interactive session on gender identity with two experts on LGBTQIA2S+ issues in medicine following a YCC Grand Rounds seminar, and 5) a Chief Fellow-led interactive session on upstander training. The DEI curriculum was mandatory for all fellows. Evaluations of the curriculum at its completion were collected via a separate online anonymous survey that included 11 questions about comfort level in addressing discrimination and harassment (Kirkpatrick level 2). Perceptions of DEI among HO fellows and Core Faculty were further gauged using annual trainee and faculty surveys distributed by the American Council of Graduate Medical Education (ACGME) in 2021 and 2022, and a separate survey designed and distributed by the Program Leadership to gauge perceptions of DEI among HO Core Faculty in 2021 and 2022. RESULTS: In total, 17 fellows (68%) responded to the pre-curriculum needs assessment survey. The majority of respondents witnessed (>75%) or experienced (>64%) some form of harassment during medical training. All respondents reported being under-equipped to navigate these scenarios. Inclusion of DEI into the fellowship curriculum was perceived as very important (mean 8.19/10, range 2-10). All fellows completed the five-part DEI curriculum. A total of 8 fellows (32%) responded to the post-curriculum survey; respondents reported an increase in comfort level navigating discrimination events (Figure 1). In ACGME trainee and faculty surveys prior to (2021) and following (2022) initiation of the DEI curriculum, compliance with DEI efforts increased above national means after initiation of the DEI curriculum (2021 mean scores, HO fellowship program vs national: faculty, 4.6 vs 4.4, fellows 4.2 vs 4.3; 2022: faculty 4.8 vs 4.5, fellows 4.6 vs 4.3). In surveys prior to and following the institution of the DEI, the percentages of HO Core Faculty who agreed that the HO Fellowship Program treats DEI as being core to its mission, on par with clinical excellence and investigative pursuits, increased from 71.4% to 80%. Those who agreed that DEI topics are formally or informally discussed as part of the educational experience of HO fellows increased from 28.5% to 50%. CONCLUSION: A DEI curriculum for HO fellows may lead to significant improvements in fellow upstander responses to discrimination in the workplace and may augment institutional perceptions of DEI among fellows and faculty. We plan to continue our fellow-led DEI curriculum in perpetuity as part of our fellowship program and institution's commitment to DEI efforts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lung cancer is the most common type of cancer and the leading cause of cancer-related mortality in the world, with over 2.1 million new cases diagnosed and 1.8 million deaths in 2018. In the United States, it is estimated that 230,000 new cases will be diagnosed in 2020 and will be responsible for 135,000–160,000 deaths. While lung cancer is the second most commonly diagnosed type of cancer in men and women behind prostate cancer and breast cancer, respectively, lung cancer remains the leading cause of cancer-related death for either gender. Neurologic complications arise from metastatic spread, paraneoplastic mechanisms, or adverse effects of lung cancer therapy. This chapter provides clinical descriptions of these complications and outlined diagnostic and therapeutic strategies.

Background: Immune checkpoint inhibitors (ICIs) have become an increasingly important tool in cancer treatment, revealing durable responses in several different types of tumors, including NSCLCs. Nevertheless, ICIs carry a risk of immune-mediated toxicities. There is a paucity of data for concurrent use of these agents in patients with autoimmune disorders, such as multiple sclerosis (MS). Case Presentation: We report a case of a man with a history of MS and metastatic NSCLC with brain metastases who had cancer progression after receiving chemotherapy, whole-brain radiation therapy, and stereotactic radiosurgery to brain lesions and was treated with the programmed death-ligand 1 inhibitor, atezolizumab. He had dramatic clinical and radiographic benefit but developed a severe MS flare and neurologic decline precluding further treatment. Considerable growth of a previously radiated brain lesion prompted resection, with pathologic findings consistent with radiation necrosis and demyelination without viable tumor cells. Conclusions: Although patients with preexisting autoimmune diseases, including MS, might be at an increased risk of developing immune-related adverse events with ICIs, they may also experience anticancer benefit. Intracranial disease can be challenging to accurately diagnose in a patient with MS who previously underwent radiation, as progressing lesions can be tumor growth, MS flare, or radiation necrosis.