70 Lymphocyte Hsp70 is a Novel Predictive Biomarker for Response to Immune Checkpoint Inhibitors in Metastatic Renal Cell Carcinoma

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Abstract Background We sought to map the immunological landscape of metastatic renal cell carcinoma (RCC) in order to understand the mechanisms that dictate response to immune checkpoint inhibitors (ICI) and uncover biomarkers for ICI response. Methods We generated a single-cell RNA sequencing (scRNA-seq) atlas of the tumors of 70 patients with RCC. 49 of the 70 patients received ICI (either anti-PD-1 alone or in combination), and most samples were taken pre-treatment (n = 48) and had clear-cell histology (n = 58). Each patient that received ICI was clinically annotated for best overall response (BOR), and for our analysis we compared patients with clinical benefit (complete or partial BOR) vs. non-clinical benefit (BOR of progressive disease). Results Differential abundance testing for immune composition between clinical benefit and non-benefit tumors revealed a population of CD4+ T cells marked by heat shock 70 family proteins (Hsp70) such as HSPA6, HSPA1A, and HSPA1B (p = 0.0015). Notably, this population was nearly universally absent in patients without clinical benefit from ICI, but found in substantial numbers (up to > 45% of all CD4+ T cells) in patients with clinical benefit. Beyond CD4+ T cells, we observed that a Hsp70 signature was significantly upregulated across the majority of immune cell populations in patients with clinical benefit vs. those without it (p < 0.05 for CD4+ T cells, CD8+ T cells, B cells, NK cells, dendritic cells, monocytes), suggesting a link between heat shock proteins and clinical benefit from ICI across immune populations. As validation, we observed higher Hsp70 levels in lymphocytes from patients with clinical benefit from ICI in an external cohort (from Bi et al., Cancer Cell, 2021), and across tumor samples taken either pre or post-treatment. Together, these findings indicate that Hsp70 expression in lymphocytes predicts response to ICI across timepoints and cohorts. In an additional cohort of RCC patients who received single agent anti-PD-1, we observed that patients with high levels of Hsp70 had >3x longer median progression-free survival (PFS) (14.3 vs. 3.9 months, p = 0.0058). Lastly, we investigated what the molecular drivers or consequences of heat shock expression may be by correlating Hsp70 activity against 50 canonical molecular (hallmark) pathways. This analysis revealed hypoxia, TNF, and IL-2 signaling were all significantly positively correlated with heat shock activity, indicating that the combination of pro-inflammatory cytokines and the presence of a hypoxic tumor-microenvironment may upregulate Hsp70 and drive response to ICI. Conclusions Using a scRNA-seq atlas of tumors from metastatic RCC, we found a novel factor, Hsp70, that in lymphocytes strongly predicts response and greatly extended PFS after ICI. Future studies will test Hsp70 as a biomarker in non-ICI contexts to evaluate its utility as a prognostic biomarker. Immunofluorescence staining will also be performed to test the clinical feasibility and specificity of using Hsp70 as a biomarker. DOD CDMRP Funding yes

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