Immune checkpoint blockade (ICB) therapy only induces durable responses in a subset of cancer patients. The underlying mechanisms of such selective efficacy remain largely unknown. By analyzing the expression profiles of immune checkpoint molecules in different statuses of murine tumors, we found that tumor progression generally randomly upregulated multiple immune checkpoints, thus increased the Heterogeneity of Immune checkpoint Signature (HIS) and resulted in immunotherapeutic resistance. Interestingly, overexpressing one pivotal immune checkpoint in a tumor hindered the upregulation of a majority of other immune checkpoint genes during tumor progression via suppressing interferon γ, resulting in HIS-low. Indeed, PD-L1 high-expression sensitized baseline large tumors to anti-PD1 therapy without altering the sensitivity of baseline small tumors. In line with these preclinical results, a retrospective analysis of a phase III study involving patients with non-small cell lung cancer (NSCLC) revealed that PD-L1 tumor proportion score (TPS) ≥ 50% more reliably predicted therapeutic response in NSCLC patients with baseline tumor volume (BTV)-large compared to patients with BTV-small. Notably, TPS combined with BTV significantly improved the predictive accuracy. Collectively, the data suggest that HIS reflects the dynamic features of tumor immune evasion and dictates the selective efficacy of ICB in a tumor size-dependent manner, providing a potential novel strategy to improve precision ICB. These findings highlight the application of ICB to earlier stages of cancer patients. The integration of PD-L1 with BTV may immediately improve patient stratification and prediction performance in the clinic.

Anti-PD-L1 therapy exhibits durable efficacy, but only in a small fraction of cancer patients. The immunosuppressive tumor microenvironment (TME) is a crucial obstacle that impedes cancer immunotherapy. Here, we found that anti-PD-L1 therapy coupled with CD4+ T cell depletion induced colorectal tumor regression and vascular normalization, while monotherapy only retarded tumor growth without affecting the tumor vasculature. Moreover, simultaneous PD-L1 blockade and CD4+ T cell depletion eradicated intratumoral PD-L1+ lymphoid and myeloid cell populations, while additively elevating the proportions of CD44+CD69+CD8+, central memory CD44+CD62L+CD8+, and effector memory CD44+CD62L-CD8+ T cells, suggesting a reduction in immunosuppressive cell populations and the activation of CD8+ T cells in the TME. Moreover, anti-PD-L1 therapy reduced the proportions of intratumoral PD-L1+ immune cells and suppressed tumor growth in a CD8+ T cell dependent manner. Together, these results suggest that anti-PD-L1 therapy induces tumor vascular normalization and colorectal tumor regression via CD8+ T cells, which is antagonized by CD4+ T cells. Our findings unveil the positive correlation of tumor regression and vascular normalization in colorectal tumor models upon anti-PD-L1 therapy, providing a potential new strategy to improve its efficacy.

Background: Dexmedetomidine is a widely used anaesthetic adjuvant for cancer resection surgeries. However, recent reports suggest that it may promote tumour growth or metastasis, so it is essential to clarify its tumour-related effects.Methods: Seven syngeneic murine tumour models were used to assess the impact of dexmedetomidine on primary tumour growth, spontaneous tumour metastasis, and surgical resection-associated metastasis. Cancer cell proliferation and apoptosis experiments, terminal deoxynucleotidyl transferase dUTP nick-end labelling assays, immune cell analysis, specific T-cell depletion experiments, and gene transcription analysis were conducted to identify the underlying mechanisms.Results: Dexmedetomidine did not affect growth of EO771 or 4T1 breast tumours, LAP0297 or LLC lung tumours, MCA205 fibrosarcoma, or their spontaneous lung metastases. It did not promote lung metastasis after breast cancer resection. Dexmedetomidine significantly suppressed MCA38 and CT26 colorectal tumour growth (P<0.01) and promoted apoptosis in MCA38 tumour tissues (P<0.05) without affecting proliferation and apoptosis of MCA38 tumour cells in vitro, suggesting indirect anti-tumour effects. Dexmedetomidine increased the proportions of intratumour CD4+ T (P<0.01), CD8+ T (P<0.001), and natural killer cells (P<0.01), and it upregulated transcription of the cytotoxicity-related genes Infg, Tnfa, and Cxcl9 (P<0.05) in MCA38 tumours. Either CD8+ or CD4+ T-cell depletion reversed the anti-tumour effects of dexmede-tomidine on MCA38 tumours (P<0.05).Conclusions: Dexmedetomidine conferred colorectal tumour-type specific suppression by modulation of tumour CD4+ and CD8+ T cells without tumour-enhancing effects.

Background Selective activation of Delta-like 1 (DLL1)-Notch signaling is a new approach to activate CD8(+) T cell and suppress tumor growth, while the efficacy remains modest. Lentinan (LNT) is a clinically used immunomodulation agent. Thus, we hypothesized that LNT could improve the efficacy of DLL1. Methods The effects of LNT combined with DLL1 on tumor growth were evaluated by growth curve and tumor weight in EO771 breast and LAP0297 lung tumor models. The impacts on immune cells and gene expression in tumor tissues were determined by flow cytometry, qPCR. Neutrophil depletion was used to investigate the mechanism of the combination therapy on tumor growth. The data sets were compared using unpaired student's t-test or ordinary one-way ANOVA. Results LNT treatments additively improved the antitumor effects of DLL1 in EO771 breast tumor growth. Remarkably, LNT treatments synergistically enhanced the suppression of DLL1 on LAP0297 lung tumor growth, resulting in tumor regression. Mechanically, the combination of LNT and DLL1 interventions not only promoted the accumulation and activation of CD8(+) T cells, but also increased intratumoral CD45(+)CD11b(+)Ly6G(+) neutrophils. Reduced neutrophils by anti-Gr1 antibody administrations reversed the improved antitumor effects by LNT treatments in LAP0297 lung tumor. These results suggest that LNT treatments improve the inhibition of DLL1 on tumor growth via neutrophils. Conclusions Our findings indicates that LNT and DLL1 may induce synergistical antitumor immunity via simultaneous modulating lymphoid and myeloid cell populations regardless of the type of tumor, providing a potential new strategy to potentiate cancer immunotherapy.

Multiple myeloma (MM) remains an incurable hematologic malignancy due to its frequent drug resistance and relapse. Cluster of Differentiation 47 (CD47) is reported to be highly expressed on MM cells, suggesting that the blockade of CD47 signaling pathway could be a potential therapeutic candidate for MM. In this study, we developed a bortezomib-resistant myeloma patient-derived xenograft (PDX) from an extramedullary pleural effusion myeloma patient sample. Notably, anti-CD47 antibody treatments significantly inhibited tumor growth not only in MM cell line-derived models, including MM.1S and NCI-H929, but also in the bortezomib-resistant MM PDX model. Flow cytometric data showed that anti-CD47 therapy promoted the polarization of tumor-associated macrophages from an M2- to an M1-like phenotype. In addition, anti-CD47 therapy decreased the expression of pro-angiogenic factors, increased the expression of anti-angiogenic factors, and improved tumor vascular function, suggesting that anti-CD47 therapy induces tumor vascular normalization. Taken together, these data show that anti-CD47 antibody therapy reconditions the tumor immune microenvironment and inhibits the tumor growth of bortezomib-resistant myeloma PDX. Our findings suggest that CD47 is a potential new target to treat bortezomib-resistant MM.

Although radiotherapy (RT) has been widely used in cancer treatment, it provides limited benefits in patients with metastatic cancers due to rare abscopal antitumor effects. Recent progress in cancer immunotherapy provides a potential new strategy to boost the abscopal antitumor effects of RT.