Clinical outcome following checkpoint therapy in renal cell carcinoma is associated with a burst of activated CD8 T cells in blood

Abstract

PurposeCheckpoint therapy is now the cornerstone of treatment for patients with renal cell carcinoma (RCC) with advanced disease, but biomarkers are lacking to predict which patients will benefit. This study proposes potential immunological biomarkers that could developed for predicting therapeutic response in patients with RCC.MethodsUsing flow cytometry, RNA sequencing, and T-cell receptor (TCR) sequencing, we investigated changes in T cells in the peripheral blood of patients with advanced RCC after receiving immunotherapy. We used immunofluorescence (IF) imaging and flow cytometry to investigate how intratumoral T cells in patients’ tumors (resected months/years prior to receiving checkpoint therapy) predicted patient outcomes after immunotherapy.ResultsWe found that a small proportion of CD4 and CD8 T cells in the blood activate following checkpoint therapy, expressing the proliferation marker Ki67 and activation markers HLA-DR and CD38. Patients who had the highest increase in these HLA-DR +CD38+CD8 T cells after treatment had the best antitumor immune response and experienced clinical benefit. Using RNA sequencing, we found that while these cells expanded in most patients, their phenotype did not drastically change during treatment. However, when we analyzed the TCR repertoire of these HLA-DR +CD38+CD8+T cells, we found that only patients who clinically benefitted had a burst of new clonotypes enter this pool of activated cells. Finally, we found that abundant T cells in the untreated tumors predicted clinical benefit to checkpoint therapy on disease progression.ConclusionsTogether, these data suggest that having a strong pre-existing immune response and immediate peripheral T-cell activation after checkpoint therapy is a predictor of clinical benefit in patients with RCC.

Peripheral blood CD3+HLADR+ cells and associated gut microbiome species predict response and overall survival to immune checkpoint blockade

“…Rather than the static CD3 + HLADR + frequencies, that can also likely depict activated T cells with impaired function unable to contribute to the antitumoral response, we also demonstrate how the dynamics of these cells, comparing early and late time-points to the baseline, can also signi cantly predict OS. Patients with increasing levels of CD3 + HLADR + levels as an immediate result of the rst cycle(s) of immunotherapy, showing an ICI-mediated activation of T cells in the peripheral blood, which may consequently transit to the tumor microenvironment and contribute to enhanced antitumoral response, had a signi cantly prolonged OS, in line with prior ndings [14]. Interestingly, this effect was most pronounced in patients undergoing dual immune checkpoint blockade with nivolumab and ipilimumab.…”

“…In squamous cell carcinoma of the lung and head and neck cancer, the same higher levels of circulating activated T lymphocytes predicted impaired overall survival [36,37]. In the ICI setting, little is known related to the biomarker role of peripheral CD3 + HLADR + cells, but Carlisle et al report how an increase of a similar cell population after the rst cycle of immunotherapy with ICI predicts better progress free-survival (PFS) and OS in RCC [14]. In our cohort, we demonstrate how the peripheral blood CD3 + HLADR + frequencies can represent strong predictors of OS, with patients with higher pretreatment levels of this molecule having an impaired response and OS to ICI therapy.…”

Unveiling the impact of tertiary lymphoid structures on immunotherapeutic responses of clear cell renal cell carcinoma

“…Together this may explain the poor prognosis of peritumoral TLS of ccRCC and attempts to reinvigorate the PD‐1 + CD8 + T cells and challenge the suppressive TME may increase patients’ sensitivity to the current immunotherapy. Other researchers found the pre‐existing tumor immunity in RCC predicts better response to ICIs therapy, which may occur in the APC‐dense niche in the TME 50 . It will be interesting to take the APC‐dense niche and TCF‐1 + CD8 T cells into the future assessment, especially when examining the SFL‐TLS.…”

“…Other researchers found the preexisting tumor immunity in RCC predicts better response to ICIs therapy, which may occur in the APC-dense niche in the TME. 50 It will be interesting to take the APC-dense niche and TCF-1 + CD8 T cells into the future assessment, especially when examining the SFL-TLS.…”

Case Report: Peripheral blood T cells and inflammatory molecules in lung cancer patients with immune checkpoint inhibitor-induced thyroid dysfunction: Case studies and literature review

“…Monitoring peripheral CD8 + T cells, in conjunction with TSH measurement, may be useful for the research and diagnosis of CITD. Recent studies demonstrate that a dynamic increase in peripheral CD8 + T cells is a valuable indicator of immune responses to ICIs in cancer patients ( 26 , 27 , 37 ). Further research is warranted to investigate the temporal and subtype changes of peripheral CD8 + T cells in order to elucidate immunotherapy-specific responses versus autoimmune responses in CITD.…”