Spatiotemporal evolution of the clear cell renal cell carcinoma microenvironment links intra-tumoral heterogeneity to immune escape

Abstract

Background Intratumoral heterogeneity (ITH) is a hallmark of clear cell renal cell carcinoma (ccRCC) that reflects the trajectory of evolution and influences clinical prognosis. Here, we seek to elucidate how ITH and tumor evolution during immune checkpoint inhibitor (ICI) treatment can lead to therapy resistance. Methods Here, we completed a single-arm pilot study to examine the safety and feasibility of neoadjuvant nivolumab in patients with localized RCC. Primary endpoints were safety and feasibility of neoadjuvant nivolumab. Then, we spatiotemporally profiled the genomic and immunophenotypic characteristics of 29 ccRCC patients, including pre- and post-therapy samples from 17 ICI-treated patients. Deep multi-regional whole-exome and transcriptome sequencing were performed on 29 patients at different time points before and after ICI therapy. T cell repertoire was also monitored from tissue and peripheral blood collected from a subset of patients to study T cell clonal expansion during ICI therapy. Results Angiogenesis, lymphocytic infiltration, and myeloid infiltration varied significantly across regions of the same patient, potentially confounding their utility as biomarkers of ICI response. Elevated ITH associated with a constellation of both genomic features (HLA LOH, CDKN2A/B loss) and microenvironmental features, including elevated myeloid expression, reduced peripheral T cell receptor (TCR) diversity, and putative neoantigen depletion. Hypothesizing that ITH may itself play a role in shaping ICI response, we derived a transcriptomic signature associated with neoantigen depletion that strongly associated with response to ICI and targeted therapy treatment in several independent clinical trial cohorts. Conclusions These results argue that genetic and immune heterogeneity jointly co-evolve and influence response to ICI in ccRCC. Our findings have implications for future biomarker development for ICI response across ccRCC and other solid tumors and highlight important features of tumor evolution under ICI treatment. Trial registration The study was registered on ClinicalTrial.gov (NCT02595918) on November 4, 2015.

High expression of PPIA associates with poor prognosis and tumor immune infiltration of gastric cancer

“…Tumor in ltrated immune cells were a vital component of tumor microenvironment and involved in tumorigenesis and progression. [44][45][46] However, the role of PPIA in modulating the immune system in GC is still elusive. Our results proved that PPIA was negatively related to ICI in GC.…”

Rationale for immune checkpoint inhibitors plus targeted therapy for advanced renal cell carcinoma

“…Besides activation of myeloid cells, drug resistance also occurs in other changes in the microenvironment, such as angiogenic gene expression and T cell infiltration. High intra-tumoral heterogeneity (ITH) shows depletion of putative neoantigens, increased myeloid activation, decreased T cell diversity, and a wealth of genomic characteristics (SETD2 and PBRM1 mutations, loss of HLA heterozygosity, and loss of CDKN2A/B), all of which are generally related to evasion of the antitumor immune response [ 101 ].…”

Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma

“…Using LOHHLA, we detected LOH of HLA in only 5.9% of tumours. It has been reported that LOH on HLA class I genes and 9p21 loss tend to co-occur 49 , suggesting a potential mechanism for immune escape. However, after adjusting for stage and grade (correlated with both LOH of HLA and 9p21 loss, Supplementary Table 14)…”