2235P - Chemotherapy priming leads to hypermutability and immune surveillance in colorectal cancer

Background

Molecular alterations generated by DNA repair deficiencies and DNA damaging agents can be detected by the host immune system and this can restrict cancer growth. We have previously reported that temozolomide (TMZ) is able to induce MMR defects and hypermutability leading to immunotherapy clinical benefit in the subset of CRCs characterized by inactivation of O6-methylguanine methyltransferase (MGMT). We reasoned that combination of chemotherapeutic agents could similarly impair DNA repair function, increase genomic diversity and trigger cancer immunogenicity in the larger group of MMR proficient (MMRp)/MGMT wild type (MGMTwt) CRCs.

Methods

We studied the impact of commonly used cytotoxic agents such as 5-fluorouracil, irinotecan, oxaliplatin, cisplatin (CDDP) and TMZ on the immunogenomic features of CRC cells. We performed a two-step experiment: first, murine CRC models were exposed to chemotherapy agents used alone or in combination in a pulsatile schedule in order to mimic drug exposure in the clinical setting (priming phase) and then injected in immune-deficient and -proficient mice (editing phase). Whole exome sequencing (WES) was performed at baseline and after both the priming and the editing phases to identify mutational signatures, neoantigen prediction and immunoediting.

Results

We found that combinatorial treatment of MMRp /MGMTwt CRC cells with CDDP and TMZ causes impairment of MMR and hypermutability, eventually leading to tumor rejection in syngeneic mice. The majority of mutations caused by CDDP-TMZ are edited by the immune system and, importantly, mice that had successfully rejected cells treated with CDDP-TMZ are vaccinated against their untreated counterpart. The same effect is not observed when CDDP and TMZ are given as monotherapy or when CRC cells are primed with the 5-fluorouracil-oxaliplatin-irinotecan (FOLFOXIRI) triplet.

Conclusions

These results indicate that rational combinations of commonly used cytotoxic agents can be exploited to promote cancer cell hypermutability and immunogenicity, and have implications in the design of new chemo-immunotherapy approaches in CRC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

University of Turin and IFOM ETS - The AIRC Institute of Molecular Oncology.

Funding

Fondazione AIRC (5 per Mille 2018 - ID. 21091 program – P.I. Bardelli Alberto); AIRC ( IG 2018 - ID. 21923 project – P.I. Bardelli Alberto); International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB) and AIRC (22795); IMI contract n. 101007937 PERSIST-SEQ; European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (TARGET, grant agreement No 101020342) - P.I. Bardelli Alberto. AIRC ( MFAG 2019 Grant-ID 24604-PI Giovanni Germano).

Disclosure

P.P. Vitiello: Financial Interests, Personal, Invited Speaker: Merck, Biocartis. B.J. Rousseau: Financial Interests, Personal, Advisory Role: Neophore; Financial Interests, Personal, Other, Travel expense: Bayer, Servier, Astellas. L.A. Diaz: Financial Interests, Personal, Stocks/Shares: PGDx, Jounce Therapeutics, Thrive Earlier Detection, Se'er, Kinnate, Neophore. F. Di Nicolantonio: Non-Financial Interests, Member of Board of Directors, I serve as a member of the Executive Board of the Italian Cancer Society (https://www.cancerologia.it/consiglio.html): Italian Cancer Society (SIC); Non-Financial Interests, Other, I am a member of the Scientific Board of Fondazione Oncology Niguarda Onlus, a charity on cancer research based in Milan (https://oncologianiguarda.org/it/la-fondazione/organi-sociali): Fondazione Oncologia Niguarda Onlus. G. Germano: Financial Interests, Personal, Stocks/Shares: Neophore. A. Bardelli: Financial Interests, Personal, Advisory Role: Illumina, Inivata; Financial Interests, Personal and Institutional, Stocks/Shares: Neophore. All other authors have declared no conflicts of interest.