Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer

Subudhi, Sumit K.; Vence, Luis M.; Zhao, Hao; Blando, Jorge; Yadav, Shalini S.; Xiong, Qing; Reuben, Alexandre; Aparicio, Ana; Corn, Paul G.; Chapin, Brian F.; Pisters, Louis L.; Troncoso, Patricia; Tidwell, Rebecca S. Slack; Thall, Peter F.; Wu, Chang-Jiun; Zhang, Jianhua; Logothetis, Christopher; Futreal, Andrew; Allison, James P.; Sharma, Padmanee

doi:10.1126/scitranslmed.aaz3577

Cited by 123 publications

(96 citation statements)

References 36 publications

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“…ICB and PVSRIPO immunotherapy engage antitumor T cell immunity 3 . Immunologically active tumors are a feature of ICBresponsive patients in other indications 14 , in some cases in patients with low TMB 18 , and very low TMB associates with increased tumor-intrinsic inflammation in rGBM (Fig. 2).…”

Section: Discussionmentioning

confidence: 99%

“…Relevant patient demographics, as well as survival information (updated as of April 29, 2020), are presented in Supplementary Table 1. Additional de-identified cohorts from previously published studies include: the MSKCC IMPACT study containing GBM patients treated with either αPD1 or αPD-L1 (in two cases with combined αCTLA4) 8 , αPD1-treated rGBM cohort (Zhao et al 10 ) 18 , the Glioma Longitudinal AnalySIS (GLASS) consortium 11 , Wang et al 16 , and TCGA.…”

Section: Methodsmentioning

confidence: 99%

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Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy

et al. 2021

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Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10–20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy

et al. 2021

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“…No differences in terms of TMB and neoantigens were found between the immune and non-immune classes in our study. Although the somatic mutation frequencies of prostate cancer are dramatically lower than those in melanoma [55], Subudhi et al [56] reported that some metastatic castration-resistant prostate cancer patients who received ipilimumab treatment can still benefit from immunotherapy, with a median number of nonsynonymous somatic mutations of 76.…”

Section: Accepted Articlementioning

confidence: 99%

Immune response drives outcomes in prostate cancer: implications for immunotherapy

Meng

Zhou

et al. 2020

Molecular Oncology

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The heterogeneity of the immune microenvironment leads to different responses in immune checkpoint blockade therapy. We aimed to propose a robust molecular classification system to investigate the relevance of the immune microenvironment subtype and prognosis of prostate cancer patients, as well as the therapeutic response to immune checkpoint blockade therapy. A total of 1,557 prostate cancer patients were enrolled, including 69 real‐world samples from our institute (titled the AHMU‐PC cohort). The non‐negative matrix factorization algorithm was employed to virtually microdissect patients. The immune enrichment was characterized by a high enrichment of T cell‐, B cell‐, NK cell‐, and macrophage‐associated signatures, by which patients were subclassified into nonimmune and immune classes. Subsequently, the immune class was dichotomized into immune‐activated and immune‐suppressed subtypes based on the stromal signature, represented by the activation of WNT/TGF‐β, TGF‐β1, and C‐ECM signatures. Approximately 14.9% to 24.3% of patients belonged to the immune‐activated subtype, which was associated with favorable recurrence‐free survival outcomes. In addition, patients in the immune‐activated subtype were predicted to benefit more from anti‐PD‐1/PD‐L1 therapy. In conclusion, our study identifies a novel immune molecular classifier that is closely related to clinical prognosis and provides novel insights into immunotherapeutic strategies for prostate cancer patients.

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“…Finally, we looked at human clinical trial data from patients with metastatic prostate cancer treated with ipilimumab (anti-CTLA-4) on a single institution clinical trial (NCT02113657; ref. 47). Published RNA expression data were used to look at RARRES2, PTEN, and PD-L1 (CD274) in these patients, and evaluate clinical outcomes.…”

Section: Expression Of Chemerin In the Tme Leads To Decreased In Vivomentioning

confidence: 99%

Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells via Modulation of a Novel CMKLR1-mediated Signaling Cascade

Rennier

Shin

Krug

et al. 2020

Clinical Cancer Research

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Purpose: Chemerin (retinoic acid receptor responder 2, RARRES2) is an endogenous leukocyte chemoattractant that recruits innate immune cells through its receptor, ChemR23. RARRES2 is widely expressed in nonhematopoietic tissues and often downregulated across multiple tumor types compared with normal tissue. Recent studies show that augmenting chemerin in the tumor microenvironment significantly suppresses tumor growth, in part, by immune effector cells recruitment. However, as tumor cells express functional chemokine/chemoattractant receptors that impact their phenotype, we hypothesized that chemerin may have additional, tumor-intrinsic effects. Experimental Design: We investigated the effect of exogenous chemerin on human prostate and sarcoma tumor lines. Key signaling pathway components were elucidated using qPCR, Western blotting, siRNA knockdown, and specific inhibitors. Functional consequences of chemerin treatment were evaluated using in vitro and in vivo studies. Results: We show for the first time that human tumors exposed to exogenous chemerin significantly upregulate PTEN expression/ activity, and concomitantly suppress programmed death ligand-1 (PD-L1) expression. CMKLR1 knockdown abrogated chemerininduced PTEN and PD-L1 modulation, exposing a novel CMKLR1/ PTEN/PD-L1 signaling cascade. Targeted inhibitors suggested signaling was occurring through the PI3K/AKT/mTOR pathway. Chemerin treatment significantly reduced tumor migration, while significantly increasing T-cell-mediated cytotoxicity. Chemerin treatment was as effective as both PD-L1 knockdown and the anti-PD-L1 antibody, atezolizumab, in augmenting T-cellmediated tumor lysis. Forced expression of chemerin in human DU145 tumors significantly suppressed in vivo tumor growth, and significantly increased PTEN and decreased PD-L1 expression. Conclusions: Collectively, our data show a novel link between chemerin, PTEN, and PD-L1 in human tumor lines, which may have a role in improving T-cell-mediated immunotherapies.

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Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer

Cited by 123 publications

References 36 publications

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy

Very low mutation burden is a feature of inflamed recurrent glioblastomas responsive to cancer immunotherapy

Immune response drives outcomes in prostate cancer: implications for immunotherapy

Chemerin Reactivates PTEN and Suppresses PD-L1 in Tumor Cells via Modulation of a Novel CMKLR1-mediated Signaling Cascade

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