Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma

Abstract

Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples we characterized CD8 + T cell gene expression across a cohort of MM patients receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8 + transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over four-fold greater, with preferential induction of mitosis and interferon related genes. Early samples from patients with durable clinical benefit demonstrated over-expression of T cell receptor (TCR) encoding genes. By mapping TCR clonality we find responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates large clones over-express genes implicated in cytotoxicity and characteristic of effector memory T cells including CCL4, GNLY, and NKG7 . The six-month clinical response to ICB in MM patients is associated with the large CD8 + T cell clone count 21 days after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8 + clonality can provide information regarding long-term treatment response and potentially facilitate treatment stratification.

Impact of PD-1 Blockade on Severity of COVID-19 in Patients with Lung Cancers

“…We prespecified four categories of prior PD-1 blockade to characterize the temporal relationship between treatment exposure and diagnosis of COVID-19: ever received PD-1 blockade, most recent dose within 6 months, most recent dose within 6 weeks, and first dose within 3 months. These definitions were selected to examine how recent and more remote exposure to PD-1 blockade might influence COVID-19 severity, cognizant of both the prolonged receptor occupancy that can persist for months (28) as well as the distinct proliferative burst in response to initially starting this therapy (18)(19)(20)(21).…”

“…As another measurement of robustness, we examined different bio-plausible (19)(20)(21)28) definitions to define the proximity of prior PD-1 blockade exposure. This included those who received PD-1 blockade at any time previously, those in whom the most recent dose of PD-1 blockade was within 6 months of COVID-19 diagnosis, those in whom the most recent dose of PD-1 blockade was within 6 weeks of COVID-19 diagnosis, or who had initiated PD-1 blockade within 3 months of COVID-19 diagnosis.…”

“…Lastly, given the dissipating pharmacodynamic impact of PD-1 blockade following the initial proliferative burst associated with early doses (18)(19)(20)(21), it is possible that any interaction of PD-1 blockadefor better or worseon severity of COVID-19 would be limited to those who recently began therapy. Some (10,(22)(23)(24), but not all (11,(25)(26)(27), initial reports of COVID-19 described signals of increased severity associated with immune checkpoint inhibitors (ICIs).…”

Identification of Co-Expressed Genes Promoting CD8+ T Cell Infiltration in Melanoma Tumor Microenvironments

“…NKG7 is one of the most expressed genes in NK cells and is essential for cytotoxic degranulation of NK cells and CD8 + T cells as well as the activation and proin ammatory response of CD4 + T cells [35] . Through mapping T cell receptor cloning, Fairfax et al found that patients who responded to immunotherapy had more CD8 + T cell-related large clones overexpressed gene NKG7 than did non-responders [36] . Although the relationship between GBP5, GZMH, PSMB10 and CD8 + T cells has not been clearly demonstrated in melanoma, some of them have been veri ed in other types of cancer.…”

Systemic Blood Immune Cell Populations as Biomarkers for the Outcome of Immune Checkpoint Inhibitor Therapies

“…It was speculated that having a high TCR clonal diversity could correlate with higher probabilities to establish efficacious anti-tumor immune responses. Consequently, several studies have indeed associated a better response to a more diverse TCR repertoire in peripheral T cells [60][61][62][63].…”