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Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell RCC-- CA209-025

ABSTRACT: Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

PROVIDER: EGAS00001004292 | EGA |

REPOSITORIES: EGA

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Project description:Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Here, we analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials of treatment with PD-1 blockade (or mTOR inhibition as control arm) by whole-exome and RNA-sequencing, integrated with immunofluorescence analysis, to define the somatic alteration landscape of late-stage ccRCC and to uncover the immunogenomic determinants of therapeutic response. While conventional genomic markers (tumor mutation burden, neoantigen load) and degree of CD8+ T cell infiltration were not associated with clinical response, we discovered numerous chromosomal alterations in advanced ccRCC associated with response or resistance to PD-1 blockade. These advanced tumors were highly CD8+ T cell infiltrated, with only 22% and 5% with an immune desert and immune excluded phenotype, respectively. Our analysis revealed that CD8+ infiltrated tumors are depleted of favorable PBRM1 mutations and are enriched for unfavorable chromosomal losses of 9p21.3 when compared to non-infiltrated tumors. These data demonstrate how the interplay of somatic alterations and immunophenotypes impacts therapeutic efficacy.

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Combined PD-L1/TGFb blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8 T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.

2023-06-16 | MSV000092193 | MassIVE

Immune Restoring (IR) CAR-T Cells Display Superior Antitumor Activity and Reverse Immunosuppressive TME in a Humanized ccRCC Orthotopic Mouse Model

Project description:Here we report a humanized clear cell renal cell carcinoma (ccRCC) orthotopic NSG-SGM3 mouse model (hccRCC-NSG-SGM3) with reconstituted human lymphocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) bearing human ccRCC skrc-59 cells under the kidney capsule. Human leukocyte antigen (HLA) matched CD34+ HSCs were used for the humanization to reduce T cell alloreactivity against skrc-59 human ccRCC cells. Tumors were collected and sorted for CD45+ tumor infiltrated leukocytes (TILs) to profile the tumor microenvironment (TME) in hccRCC-NSG-SGM3. By comparing to patient data from prospective clinical trials of the anti-PD-1 monoclonal antibody (mAb) nivolumab in advanced ccRCC, the results demonstrated that the CD45+ TILs from hccRCC-NSG-SGM3 reconstitutes most CD45+ cell types, including NK cells, dendritic cells, exhausted CD8 T cells, regulatory T cells (Tregs), that are observed in advanced ccRCC patient TME. Furthermore, Anti-carbonic anhydrase IX (CAIX) G36 immune restoring (IR) chimeric antigen receptor (CAR) T cells secreting PD-L1 targeted immune checkpoint inhibitor (ICI) mAb (G36-PDL1) exhibited superior tumor control compared to G36 CAR-T cells with anti-SARS mAb (G36-SARS) and anti-BCMA A716 CAR-T cells with anti-PD-L1 mAb (A716-PDL1). In addition, G36-PDL1 CAR-T cells restored active anti-tumor immunity at tumor site uncovered by 10X genomics single cell RNA sequencing (scRNA-seq) and single cell T cell receptor sequencing (scTCR-seq).

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High Response Rate to Anti PD-1 Therapy in Desmoplastic Melanoma

Project description:<p>Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by dense fibrous stroma, resistance to chemotherapy and a lack of actionable driver mutations, but is highly associated with ultraviolet light DNA damage. We analysed 60 patients with advanced DM treated with programmed cell death 1 (PD-1) or PD-1 ligand (PD-L1) blocking antibody therapy. Objective tumor responses were observed in 42 of the 60 patients (70%, 95% confidence interval 57-81%), including 19 patients (32% overall) with a complete response. Whole-exome sequencing revealed a high mutational load and frequent NF-1 mutations (14 out of 17 cases). Immunohistochemistry (IHC) analysis from 19 DM and 13 non-DM revealed a higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with increased CD8 density and PD-L1 expression in the tumor invasive margin. Therefore, patients with advanced DM derive significant clinical benefit from PD-1/PD-L1 immune checkpoint blockade therapy despite being a cancer defined by its dense desmoplastic fibrous stroma. The benefit is likely derived from the high mutational burden and a frequent pre-existing adaptive immune response limited by PD-L1 expression.</p>

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Soluble immune-checkpoint factors as a complementary biomarker for PD-1 blockade reflect exhaustion of antitumor immunity

Project description:BACKGROUND. Precise stratification of patients with non–small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy. METHODS. We measured soluble (s) forms of the PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. Prospective biomarker finding trial (cohort A), 50 patients with pretreated NSCLC received nivolumab. In cohort B to E, retrospective observational study, soluble immune checkpoint molecules were evaluated for patients with advanced NSCLC treated with any PD-1/PD-L1 blockade (cohort B and C), cytotoxic chemotherapy (D) or targeted therapy (E). Blood samples were obtained from all patients and soluble immune checkpoint molecules were evaluated using a highly sensitive chemiluminescence-based assay. RESULTS. Nonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such correlation was not observed in patients treated with cytotoxic chemotherapy or targeted therapies. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the three soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of sPD-L1 and sCTLA-4 efficiently discriminated responsiveness among patients with immune-reactive tumors. CONCLUSION. Combinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest such a combination might provide a biomarker complementary to tPD-L1 for NSCLC patients.

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Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in Colorectal Cancer

Project description:Expanding the efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC) patients presses for a comprehensive understanding of treatment responsiveness. Here, we analyzed 169 single-cell samples from CRC patients at multiple sequential time points during the course of anti-PD-1 neoadjuvant therapy to map the evolution of local and systemic immunity. In tumors, exhausted T (Tex) cells or tumor-reactive-like CD8 T (Ttr-like) cells were closely related to treatment efficacy, and we observed correlated dynamics between Tex cells and multiple other tumor-enriched cell types following the treatment. Accordingly, several coordinated cellular programs exhibiting distinct response associations were identified. From a systemic perspective, we found divergent replenishment patterns of Ttr-like cells underlying different response statuses and decoded the phenotypic transitions of Ttr-like cells as they infiltrated tissues from the periphery. Finally, a predictive signature was established using circulating CD8 T cells. Our study provides novel insights into the spatiotemporal cellular dynamics following PD-1 blockade in CRC.

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