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Poster session 14

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

Date

10 Sep 2022

Session

Poster session 14

Topics

Tumour Immunology;  Immunotherapy

Tumour Site

Presenters

Helena Oliveres

Citation

Annals of Oncology (2022) 33 (suppl_7): S331-S355. 10.1016/annonc/annonc1058

Authors

H. Oliveres1, C. Foguet2, M. Nebozhyn3, L. Pedrosa1, I. Cirrincione4, P. Morales5, J. Lunceford6, T. Gorria1, J. Maurel7, M. Cascante8

Author affiliations

  • 1 Medical Oncology, Hospital Clinic y Provincial de Barcelona, 08036 - Barcelona/ES
  • 2 Faculty Of Biology, Department of Biochemistry and Molecular Biomedicine & Institute of Biomedicine of Universitat de Barcelona, 08028 - Barcelona/ES
  • 3 Medical Scientific Liaison, Merck & Co. Inc., 17868 - Riverside/US
  • 4 Medical Scientific Liaison, MSD, 08029 - Barcelona/ES
  • 5 Medical Department, MSD - Merck Sharp & Dohme de Espana S.A., 28027 - Madrid/ES
  • 6 Medical Advisor, Merck S.L.U., 2000 - Washington/US
  • 7 Medical Oncology Department, Hospital Clinic y Provincial de Barcelona, 08036 - Barcelona/ES
  • 8 Department Of Biochemistry And Molecular Biomedicine, Institute Of Biomedicine Of Universitat De Barcelona (ibub), Barcelona University, 08007 - Barcelona/ES
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Abstract 763P

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 TcellinfGEP 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 TcellinfGEP 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 (TcellinfGEP 1st and IMMETCOLS 2nd tertile). TcellinfGEP and IMMETCOLS scores were calculated as a weighted sum of normalized expression values.

Results

The IMMETCOLS sig. showed a positive correlation to TcellinfGEP (rs 0.667) but not with TMB (rs 0.085). Only 1% of patients were in the TcellinfGEP low/IMMETCOLS high group, suggesting that mitochondrial metabolism constitutes the main metabolic pathways in pts with TcellinfGEP low sig. The results of joint modeling with the TcellinfGEP, 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 TcellinfGEP sig., but contain information negatively associated with clinical outcome that is orthogonal to the TcellinfGEP that may be associated with resistance. We suggest, that blocking mitochondrial metabolism/electron transport chain in TcellinfGEP low pts and also in refractory to ICI Tcellinf 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.

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