Cancer immunology research最新文献

Tumor-specific CD8+ T cells in blood seem to be important for and predictive of response to anti-PD-1 therapies. However, as most tumor antigens are unique to a given patient, the identification of tumor-specific CD8+ T cells is not routinely feasible. In this study, we characterized polyomavirus-specific CD8+ T cells from the blood of 17 patients with virus-driven Merkel cell carcinoma. We identified a 98-gene signature [Signature of Peripheral Tumor-specific CD8+ T cells (SPoTT)] that discriminated circulating tumor-specific CD8+ T cells from other T cells in immunotherapy-naïve patients. We observed profound transcriptomic differences among tumor-specific CD8+ T cells from blood versus those from tumor. In validation cohorts of Merkel cell carcinoma, as well as neoantigen-driven cancers, the signature of peripheral tumor-specific CD8+ T cells was able to identify viral oncoprotein- and neoantigen-specific CD8+ T cells with both sensitivity and specificity above 75%. We also tested a previously described 151-gene signature (NeoTCRPBL) trained on neoantigen-specific CD8+ T cells and found it was able to recognize Merkel cell polyomavirus-specific T cells with a sensitivity of 66% and a specificity of 88%. These findings show that circulating tumor-specific CD8+ T cells share fundamental characteristics across diverse tumor antigen types. More broadly, insights into antitumor T cells gained from virus-driven cancers are also likely to be relevant in mutationally driven cancers.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of cancer. However, the durable response to this therapy remains low, and there is a risk of moderate-to-severe toxicities following treatment that requires close monitoring. Over the past decade, we have learned that cytokines play an important role in mediating CAR T cell-associated toxicities and efficacy. As such, cytokine modulation has become a popular area of investigation to improve therapeutic responses. Although the relationship of many cytokines with CAR T-cell therapy has been investigated, several recent studies suggest paradoxical roles for cytokines such as IFNγ, IL2, IL4, and IL10 in CAR T-cell response and toxicity. In this review, we summarize the history of these cytokines in immunotherapies, detail the contexts in which these cytokines have been beneficial or harmful in the context of CAR T-cell therapy, and discuss factors that may be dictating their pleiotropy.

Immune checkpoint blockade (ICB) has transformed colorectal cancer therapy, yet the majority of microsatellite-stable colorectal cancers remain refractory because of insufficient tumor-immune cell cross-talk. Identifying molecular regulators that modulate the tumor immune microenvironment (TIME) is crucial for expanding ICB efficacy. In this study, we identified HNRNPA2B1, an RNA-binding protein prominently upregulated in colorectal cancer, as a key driver of immune evasion. Despite low cytotoxicity to normal cells, HNRNPA2B1 rewired the TIME by suppressing Cxcl9/Cxcl10-Cxcr3 signaling, CD8+ T-cell infiltration, and MHC class I antigen presentation, resulting in a noninflamed ("cold") tumor state. HNRNPA2B1 deletion reprogramed the TIME, enhanced CD8+ T cell-mediated tumor clearance, and sensitized microsatellite-stable colorectal cancers to ICB. A computational A2B1 score was developed to quantify HNRNPA2B1's impact on tumor-immune interactions, and it strongly correlated with immune infiltration, epithelial-mesenchymal transition status, and patient prognosis, supporting its potential role as a biomarker for ICB responsiveness in colorectal cancer.

NK cells play a critical role in anticancer immunity through their direct cytotoxicity and production of cytokines, such as FMS-like tyrosine kinase 3 ligand (Flt3L). NK cell production of Flt3L controls conventional type I dendritic cell (cDC1) abundance in the tumor and promotes protective immune responses. In this study, we show that NK cell production of Flt3l in the tumor is regulated by activation and that activation by IL2 and IL15 uniquely induced Flt3L expression in NK cells. In melanoma, IL2 signaling in NK cells led to increased Flt3L production, which boosted cDC1 abundance in the tumor and improved anti-PD-1 immunotherapy response. Furthermore, NK cell subsets differentially regulated Flt3l in the tumor, with CD11b-CD27+ NK cells in mouse tumors enriched for IL2 family signaling and upregulating Flt3l upon activation. Consistently, human CD56brightCD16- NK cells more strongly correlated with cDC1 and FLT3LG expression than other NK cell subsets across multiple human melanoma datasets and cancer indications. This mechanistic study of NK cell regulation of FLT3LG and control of the NK cell-cDC1 axis provides insights and strategies for the development of more effective cancer immunotherapies.

While the role of neutrophils in modulating antitumor T cell responses has been extensively studied, their direct effects on tumor cells remains less well understood. In this study, we investigated whether neutrophils have the capacity to directly kill tumor cells independently of T cells. We found that anti-CD40-based therapy, when combined with interleukin 10 (IL-10) receptor blockade initiates a Batf3-dependent pathway in which IL-12 and interferon gamma (IFNγ) secretion results in oncolytic neutrophil activity. Using a combination of microscopy, single-cell, and functional assays, we observed that killing of tumor cells by neutrophils is dependent on physical contact and degranulation. This degranulation-mediated killing is associated with an atypical dynamic invasive neutrophil phenotype. In line with our preclinical findings, our phase 1 trial of anti-CD40 shows that circulating IL-12, IFNγ, and IL-10 increase in response to anti-CD40, while our phase 1b/2 PRINCE study shows that lower circulating IL-10 is associated with favorable overall survival specifically among anti-CD40-treated patients. Finally, we found that neutrophil expansion with granulocyte colony stimulating factor (G-CSF) is associated with improved overall survival, specifically in patients treated with anti-CD40, suggesting that this pathway may be amenable to therapeutic intervention in patients with advanced cancer.

Relapsed and refractory Diffuse Large B-Cell Lymphoma (rrDLBCL) presents a significant challenge in hematology-oncology, with approximately 30-40% of DLBCL patients experiencing relapse or resistance to treatment. This underscores the urgent need to better understand the molecular mechanisms governing therapeutic resistance. Signal Transducer and Activator of Transcription 6 (STAT6) has been previously identified as a gene with recurrent D419 gain-of-function mutations in rrDLBCL. We demonstrated previously that when STAT6D419 mutations are present in DLBCL tumor cells, transcription of the chemokine CCL17 (aka TARC) is increased, and tumors have increased infiltration of CD4+ T cells. However, the implication of increased T cell infiltration has not been reported previously. In the present study, we developed a mouse model of STAT6D419N mutant DLBCL that recapitulates the critical features of human STAT6D419 mutant DLBCL, including increased expression of phospho-STAT6, increased CD4+ T cell invasion, and resistance to doxorubicin treatment. We report CD4+ T cells in STAT6D419N tumors exbihit higher expression of the receptor for CCL17, CCR4. Using ex vivo functional assays we demonstrated that STAT6D419N tumor cells are directly chemoattractive to CCR4+ CD4+ T cells, and CCR4 inhibition using a small molecule antagonist reduced CD4+ T cell infiltration into STAT6D419N tumors, and made STAT6D419N tumors regain therapeutic sensitivity to doxorubicin. Using PhenoCycler imaging of human rrDLBCL samples, we found that STAT6D419 tumors have increased expression of phospho-STAT6 and increased cellular interactions between phospho-STAT6+ tumor cells and CD4+/ CCR4+ CD4+ T cells. Thus, our data identify CCR4 as atherapeutic target in STAT6D419 mutant rrDLBCL.

Tumor cells employ metabolic mechanisms to limit antitumor immunity and promote resistance to immunotherapy. However, how immunotherapy modulates tumor metabolism remains unclear. Here, we demonstrated that anti-PD-1 treatment regulated cholesterol biosynthesis in cancer cells through the effector cytokine interferon IFN-γ. Mechanistically, IFN-γ-induced IRF1 transcriptionally suppresses the expression of SREBF2, a master regulator of cholesterol synthesis. Reduced cholesterol content inhibited tumor growth and sensitized tumor cells to statins, drugs lowering cholesterol. Overall, our study reveals that IFN-γ-mediated inhibition of cholesterol biosynthesis in tumor cells is an important antitumor mechanism of immunotherapy.

Adoptive transfer of T lymphocytes specific for tumor-associated neoantigens can elicit immunity against solid tumors in patients. However, how these antigens impact T cell function, effector differentiation, and persistence remains unclear. We examined how an identical CD8+ T cell product was shaped by melanoma expressing either a low-avidity tumor-associated antigen or high-avidity neoantigen, and kinetically profiled T cell differentiation in these two contexts across host tissues. High-avidity neoantigen expression was sufficient to activate naïve CD8+ T cells - leading to robust tumor regression and long-term protective immunity upon tumor rechallenge. Mechanistically, transferred naïve CD8+ T cells reacting to high-avidity neoantigen exhibited enhanced cytokine production, heightened effector function, and sustained persistence compared to the low-avidity wild-type tumors. Antitumor activity to these high-avidity tumors was preserved even in the absence of functional host T and B lymphocytes, and early lymph node trafficking was found to be essential for ACT efficacy. Expanded effector or stem-memory T cells were compared to the naïve pmel-1 T cell product. Stem-memory but not effector-memory cells exhibited similar antitumor efficacy and lymph node trafficking patterns to the naïve cells in mice with high-avidity neoantigen tumors. These findings highlight how differential tumor antigens shape divergent cellular fate and uncover a critical role of T cell trafficking in lymph nodes in shaping high-avidity neoantigen-specific antitumor responses.

Despite advances in cancer immunotherapy, treatment response is still highly variable. One contributing factor is the tumor microenvironment and specifically the presence of suppressive immune cells such as regulatory T (Treg) cells. Being able to target these specifically, while leaving effector T-cell populations untouched, is an attractive strategy that may overcome some of these issues, improving responses. To generate antibodies specific for tumor-associated Tregs, lymphocytes were isolated from tumor-bearing mice and panned against the n-CoDeR phage antibody library. Using the target-agnostic F.I.R.S.T. discovery platform, they were evaluated in ex vivo and in vivo models to determine tissue and cell selectivity and specificity and ability to deplete Tregs and elicit tumor control in subcutaneous tumor models. A total of 24 antibodies were identified and explored, representing a range of specificities from pan-T cell to Treg and tumor Treg specific. Relative expression/binding of these mAbs on tumor Tregs was not a predictor of subsequent Treg deletion efficacy or tumor control, whereas tumor Treg selectivity was. One mAb in particular demonstrated tumor-specific depletion of Tregs, leaving those in the spleen and blood untouched. This Fc:FcγR-mediated tumor-specific Treg depletion was important for antitumor effects. Target deconvolution showed that this mAb binds a distinct epitope within ICAM-1, which is hypothesized to mediate its selectivity toward tumor Tregs. These data validate the target-agnostic discovery approach as a viable means to identify new therapeutic antibodies.