1660O - Dual immune checkpoint blockade induces analogous alterations in the intratumoral CD8+ T cell and Treg compartments

Background

Immune checkpoint blockade therapies have shown clinical activity in a range of human cancer types. While the capacity of T cells to recognize tumor antigens appears a critical driver of therapy response, the alterations in T cell state that are associated with response to immune checkpoint blockade are not well understood.

Methods

To dissect the effect of neoadjuvant PD-1 and CTLA4 blockade on the intratumoral T cell population in head and neck squamous cell carcinoma (HNSCC), we performed single cell RNA and TCR sequencing on the immune infiltrates of HNSCC samples derived from treatment-naïve patients that were enrolled in the IMCISION trial treated with neoadjuvant Nivolumab (anti-PD1, 3 mg/kg, weeks 1&3) and Ipilimumab (anti-CTLA4, 1mg/kg, week 1) prior to surgery (week 4). The intratumoral T cell population was analyzed in matched pre- and on-treatment tumor biopsies from 1 partial (PR) and 10 major pathological responding (MPR) patients and 7 non-responding patients. MPR was defined as ≤10% and PR was defined as ≤50% but >10% residual viable cancer cells in the surgical resection specimen.

Results

At baseline, a subset of 4-1BB⁺ regulatory CD4⁺ T cells (activated Tregs) was more abundant in responding than non-responding tumors. Furthermore, upon therapy, this activated Treg population showed a profound decrease in responding patients. In an analogous process, intratumoral dysfunctional T cells in the CD8⁺ T cell compartment transitioned to a state of reduced activity and reduced dysfunction upon therapy. Next to these concurrent changes in the activated Treg and dysfunctional CD8⁺ compartments, the abundance of a separate transitional CD8⁺ T cell population with low levels of dysfunction increased substantially upon therapy, presumably because of increased T cell entry.

Conclusions

Together, these data demonstrate that the presence of an activated Treg compartment at baseline may predict response to dual PD-1 and CTLA4 blockade in HNSCC, and that this combination therapy results in a parallel remodeling of both the intratumoral Treg and dysfunctional CD8+ T cell compartments.

Clinical trial identification

Vos et al. Nat Commun. 2021 Dec 22;12(1):7348, NCT04620200.

Editorial acknowledgement

Legal entity responsible for the study

The Netherlands Cancer Institute (NKI) (Antoni van Leeuwenhoek), Charlotte L. zuur.

Funding

Bristol Myers Squibb (BMS).

Disclosure

C.L. Zuur: Financial Interests, Institutional, Funding: Bristol Myers Squibb (BMS). All other authors have declared no conflicts of interest.