763P - Combined gene signature (T-cell inflamed gene expression profile – TcellinfGEP – & IMMETCOLS) identifies a metabolic rewiring program, key for immune evasion

Background

The intrinsic and acquired resistance to immune checkpoint inhibitors (ICI) is a fact. We propose an immune-metabolic signature (IMMETCOLS sig.) that distributes patients (pts) across 11 tumors in 3 clusters (IMC1-3); IMC1 has more immune-suppressive score, despite higher PD1 and PD-L1 expression and IMC3, more metabolic flexibility in terms of glycolysis/mitochondrial respiration capacities. We hypothesize that our sig. in combination with Tcell_infGEP and tumor mutational burden (TMB) can better identify pts for ICI.

Methods

We analyzed 303 samples treated with pembrolizumab: melanoma (89), head & neck carcinoma (109) and pan-tumor (105) in 4 Keynote studies (KN001/006/012/028). 21 of our 38-gene IMMETCOLS sig. (mostly upregulated in IMC1) were available on the Nanostring CodeSet, and we evaluated the impact of this 21 gene IMMETCOLS and Tcell_infGEP sig. We evaluated both by testing for associations with best overall response (BOR) or/and progression free survival (PFS) using continuous sig. scores and evaluating response rates in quadrants defined by cut-offs (Tcell_infGEP 1^st and IMMETCOLS 2^nd tertile). Tcell_infGEP and IMMETCOLS scores were calculated as a weighted sum of normalized expression values.

Results

The IMMETCOLS sig. showed a positive correlation to Tcell_infGEP (r_s 0.667) but not with TMB (r_s 0.085). Only 1% of patients were in the Tcell_infGEP low/IMMETCOLS high group, suggesting that mitochondrial metabolism constitutes the main metabolic pathways in pts with Tcell_infGEP low sig. The results of joint modeling with the Tcell_infGEP, a process by which sensitizing dimensions of IMMETCOLS is detrended from the test of association, showed a non-statistically significant trend towards the hypothesized negative association of IMMETCOLS to BOR and PFS.

Conclusions

IMMETCOLS score has a substantial correlation with Tcell_infGEP sig., but contain information negatively associated with clinical outcome that is orthogonal to the Tcell_infGEP that may be associated with resistance. We suggest, that blocking mitochondrial metabolism/electron transport chain in Tcell_infGEP low pts and also in refractory to ICI Tcell_inf GEP high pts would be a promising strategy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Nebozhyn: Financial Interests, Institutional, Advisory Board: Merck. I. Cirrincione: Financial Interests, Institutional, Advisory Board: MSD. P. Morales: Financial Interests, Institutional, Advisory Board: MSD. J. Lunceford: Financial Interests, Institutional, Advisory Board: Merck. All other authors have declared no conflicts of interest.