2239P - Gene expression profiling in tumors with and without tertiary lymphoid structures across cancer-types

Background

The presence of tertiary lymphoid structures (TLS) in the tumor microenvironment (TME) is linked to favorable clinical outcomes and response to immunotherapy in various types of cancer. However, accurately measuring TLS can be difficult. Thus, our aim was to identify genes or gene expression signatures that can effectively indicate TLS abundance in the TME, irrespective of the cancer type.

Methods

Patients (pts) with advanced solid cancer participating in the molecular prescreening of the SOLTI-1904-ACROPOLI study were included. Pathological analysis was performed to determine the presence of tumor infiltrating lymphocytes (TILs) and TLS. On the same FFPE tumor block, gene expression (GE) was evaluated in all pts using a panel of 72 genes. Further GE was analyzed in a subset of 142 pts (n=66 TLS-negative, n=76 TLS+) using a panel of 192 genes, including the HER2DX 14-gene B-cell/IgG (IGG) signature. The association between GE and TLS was analyzed.

Results

1,003 pts were included across 39 different cancer-types. TLS were successfuly evaluated in 898 pts (89%). TLS were detected in 76 pts (8.5%), mostly in samples from primary tumors (n=63, 83%). Most frequent TLS+ cancer-types were colorectal (n=22), pancreatic (n=13), gastric (n=11) and breast (n=9). Compared to TLS-negative tumors, TILs were significantly higher in TLS+ tumors (median 4% vs 18%, p<0.001). The presence of TLS was significantly associated with higher expression of genes related to B-cells (CD19) and T-cells (CD4, CD8A), and lower expression of proliferation genes (TYMS, CDCA1). Upon further evaluation of GE, TLS+ tumors had a significant enrichment of genes related to activated B-cells (CD79A) and immunoglobulins (IGJ, IGKC). Finally, the IgG signature as a continuous variable demonstrated a significant association with TLS presence, independently of the cancer-type and TILs (p=0.002). In IgG-high tumors, the proportion of TLS+ tumors was 61.6% compared to 38.4% TLS-negative (p<0.001)

Conclusions

The B-cell/IGG signature is a GE pattern strongly associated with TLS across cancer types, even independently of TILs. This signature could serve as a valuable tool for precisely measuring TLS and predicting clinical outcomes and response to immunotherapy in cancer patients.

Clinical trial identification

NCT04802876.

Editorial acknowledgement

Legal entity responsible for the study

SOLTI.

Funding

Novartis Pharma AG.

Disclosure

E. Segui Solis: Financial Interests, Personal, Invited Speaker: Novartis, Veracyte, Pfizer; Financial Interests, Personal, Full or part-time Employment: SOLTI; Financial Interests, Personal, Research Grant: Amgen. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/AstraZeneca/Veracyte/Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech, Novartis. F. Brasó-Maristany: Financial Interests, Personal, Advisory Board: Reveal Genomics. E. Felip: Financial Interests, Personal, Advisory Board: AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Gilead, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Novartis, Peptomyc, Regeneron, Sanofi, Takeda, Turning Point, Pfizer; Financial Interests, Personal, Invited Speaker: Amgen, Daiichi Sankyo, Genentech, Janssen, Medical Trends, Medscape, Merck Serono, PeerVoice, Pfizer, Sanofi, Takeda, Touch Oncology, AstraZeneca, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Merck Sharp & Dohme; Financial Interests, Personal, Member of Board of Directors, Independent member: Grifols; Financial Interests, Institutional, Local PI, Clinical Trial: AstraZeneca AB, AbbVie, Amgen, Bayer Consumer Care AG, Beigene, Boehringer Ingelheim GmbH, Bristol Myers Squibb International Corporation, Daiichi Sankyo Inc., Exelixis Inc., F. Hoffmann-La Roche Ltd., Genentech Inc., GSK Research and Development Limited, Janssen Cilag International NV, Merck Sharp & Dohme Corp., Merck KGAA, Mirati Therapeutics Inc., Novartis Pharmaceutica SA, Pfizer, Takeda Pharmaceuticals International; Non-Financial Interests, Leadership Role, President (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica); Non-Financial Interests, Member, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform); Non-Financial Interests, Member, Member of the Scientiffic Advisory Committee: CAC Hospital Universitari Parc Taulí. E. Garralda: Financial Interests, Personal, Advisory Board: Roche, Ellipses Pharma, Boehringer Ingelheim, Janssen Global Services, Seattle Genetics, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Hengrui, F-Star Therapeutics, Sanofi, Incyte; Financial Interests, Personal, Invited Speaker: MSD, Lilly, Roche, Thermo Fisher, Novartis, Seagen; Financial Interests, Personal, Full or part-time Employment: NEXT Oncology; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho; Financial Interests, Institutional, Research Grant: Beigene, Janssen. L. Paz-Ares: Financial Interests, Personal, Advisory Board, Speaker fees: Roche, MSD, BMS, AZ, Lilly, PharmaMar, Beigene, Daiichi Sankyo, Medscape, PER; Financial Interests, Personal, Advisory Board: Merck Serono, Pfizer, Bayer, Amgen, Janssen, GSK, Novartis, Takeda, Sanofi, Mirati; Financial Interests, Personal, Other, Board member: Genomica, Altum sequencing; Financial Interests, Institutional, Coordinating PI: Daiichi Sankyo, AstraZeneca, Merck Sharp & Dohme Corp., BMS, Janssen-Cilag international NV, Novartis, Roche, Sanofi, Tesaro, Alkermes, Lilly, Takeda, Pfizer, PharmaMar; Financial Interests, Personal, Coordinating PI: Amgen; Financial Interests, Other, Member: AACR, ASCO, ESMO; Financial Interests, Other, Foundation Board Member: AECC; Financial Interests, Other, President: ASEICA(Spanish Association of Cancer Research): ASEICA; Financial Interests, Other, Foundation President: ONCOSUR; Financial Interests, Other, member: Small Lung Cancer Group. R. Mesia Nin: Financial Interests, Personal, Advisory Board: Merck, MSD, Bayer, Seattle Genetics, Nanobiotix, Boehringer Ingelheim, Seagen; Financial Interests, Personal, Invited Speaker: Merck, MSD, BMS; Non-Financial Interests, Principal Investigator, Clinical Trial PI: BMS; Non-Financial Interests, Principal Investigator, Observational trial PI: Merck. A.M. Arance Fernandez: Financial Interests, Personal, Advisory Board, Consultant /Advisory/Speaker/Travel, Accommodation, Expenses/: Pierre Fabre, Novartis, Roche, BMS, MSD, Merck, Sanofi; Financial Interests, Institutional, Other, Research Funding: Pierre Fabre, Novartis, MSD, BMS, Merck, Roche, Sanofi, Amgen. A. Cervantes: Financial Interests, Institutional, Advisory Board: Merck Serono, Amgen, Roche, Transgene, AnHeart Therapeutics, AbbVie, GSK; Financial Interests, Institutional, Invited Speaker: Amgen, Roche, Merck Serono, Foundation Medicine; Financial Interests, Personal, Other, Associate Editor: Annals of Oncology, ESMO Open; Financial Interests, Personal, Other, Editor in Chief: Cancer Treatment Reviews; Financial Interests, Institutional, Research Grant, Principal Investigator: Actuate Therapeutic, Amgen, Astellas Pharma, Beigene, Bayer, AstraZeneca, BMS, Amcure, FibroGen, Lilly, Genentech, MedImmune, Merck Serono, Novartis, Natera, MSD, Servier, Sierra Oncology, Adaptimmune, Takeda, Affimed, Roche, Seamless, Gilead, Janssen, F. STAR Therapeutics, Ribon Therapeutics; Non-Financial Interests, Other, Scientific Director: INCLIVA Biomedical Research Institute. J. Martin-Liberal: Financial Interests, Personal, Invited Speaker: Astellas, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, Pierre Fabre, Roche, Sanofi, Highlight Therapeutics; Financial Interests, Personal, Other, Travel grant: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Ipsen. J. Gavilá-Gregori: Financial Interests, Personal, Advisory Board: Novartis, Lilly, Pfizer; Financial Interests, Personal, Speaker, Consultant, Advisor: Novartis, Pfizer, Roche, MSD. J. Tabernero: Financial Interests, Personal, Advisory Board, scientific consultancy role: Orion Biotechnology, Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, TheraMyc, Hutchinson MediPharma International, Scandion Oncology, Ona Therapeutics, SOTIO Biotech, Inspirna Inc., Scorpion Therapeutics, Tolremo Therapeutics; Financial Interests, Personal, Invited Speaker, Educational Collaboration: Medscape Education, Physicians Education Resource (PER), PeerView Institute for Medical Education, Imedex/HMP; Financial Interests, Personal, Invited Speaker, Educational Collaboration: MJH Life Sciences; Financial Interests, Personal, Advisory Board: Cardiff Oncology; Financial Interests, Personal, Stocks/Shares: ONIRIA Therapeutics; Financial Interests, Institutional, Research Grant, ACRCelerate: Colorectal Cancer Stratified: Fundación Científica de la Asociación Española Contra el Cáncer; Financial Interests, Institutional, Research Grant, OPTIMISTICC: Opportunity to Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer: Cancer Research UK; Financial Interests, Institutional, Funding, Clinical Trials & Research: Amgen Inc., Array Biopharma Inc., AstraZeneca Pharmaceuticals LP, Bristol Myers Squibb International Corporation, Celgene International SARL, Debiopharm International SA, F. Hoffmann-La Roche Ltd., Genentech Inc., Janssen-Cilag International NV, Merck Health KGAA, Merck, Sharp & Dohme de España, SA, Novartis Farmacéutica SA, PharmaMar SA, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA, Inc., BeiGene, Boehringer Ingelheim, HalioDX SAS, Hutchinson Medipharma, MedImmune, Menarini, Merus N V, Pfizer, Mirati; Non-Financial Interests, Member of Board of Directors, Board of Directors: Cancer Core Europe, Spanish Association Against Cancer -AECC; Non-Financial Interests, Member of Board of Directors, General Assembly: Horizon Europe Cancer Mission; Non-Financial Interests, Leadership Role, External Scientific Committee: Institute for Health Research INCLIVA – Clinical Hospital of Valencia, IdiSNA –Universidad de Navarra; Non-Financial Interests, Leadership Role, Scientific Advisory Board: Spanish National Cancer Research Centre (CNIO); Non-Financial Interests, Advisory Role, International Scientific Evaluation Committee: Bosch Health Campus (BHC); Non-Financial Interests, Advisory Role, Review Board: National Decade Against Cancer (NCT) - German Consortium for Translational Cancer Research (DKTK); Non-Financial Interests, Advisory Role, Scientific Advisory Board: Karolinska Comprehensive Cancer Centre; Non-Financial Interests, Advisory Role, International Review Committee (IRC): Oncode Institute; Non-Financial Interests, Advisory Role, Scientific Advisory Board (SAB): Oslo University Hospital Comprehensive Cancer Centre (OUH CCC); Non-Financial Interests, Leadership Role, Governance Advisory Committee: European Organization for Research and Treatment of Cancer -EORTC; Non-Financial Interests, Leadership Role, Vice Chairman: World Innovative Networking (WIN) Consortium in Personalized Cancer Medicine; Non-Financial Interests, Other, Coordinating PI & Steering Committee Member. Clinical Trials & Research: AstraZeneca Pharmaceutical LP, Array Biopharma Inc., Boehringer Ingelheim, MedImmune, Menarini, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Pfizer, Servier; Non-Financial Interests, Principal Investigator, Clinical Trials & Research: Array Biopharma Inc., AstraZeneca Pharmaceutics LP, BeiGene, Boehringer Ingelheim, Debiopharm International SA, Bristol Myers Squibb International Corporation, Celgene International SARL, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Menarini, MedImmune, Merck Healthcare KGAA, Merck, Sharp & Dohme de España SA, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Sanofi-Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc.; Non-Financial Interests, Other, Steering Committee Member. Clinical Trials & Research: Debiopharm International SA, F. Hoffmann-La Roche Ltd., Genentech Inc., HalioDX SAS, Hutchinson Medipharma, Janssen-Cilag International NV, Merus NV, Taiho Pharma USA Inc.; Non-Financial Interests, Other, Coordinating PI. Clinical Trials & Research: Mirati; Non-Financial Interests, Member: AACR, ASCO, EACR, EORTC, SEOM; Other, President: Oncology Master Plan – Catalonia Department of Health; Other, Advisory Committee: Advisory Committee on Pharmaceutical Provision Financing under the Spanish National Health System. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer Ingelheim, Medica Scientia Innovation. Research; Financial Interests, Personal, Advisory Board: AstraZeneca, 1TRIALSP, S.L.; Financial Interests, Personal, Member of Board of Directors, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics, International Oncology Bureau, S.L.; Financial Interests, Institutional, Local PI: Roche, AstraZeneca; Financial Interests, Personal and Institutional, Steering Committee Member: Daiichi Sankyo; Financial Interests, Institutional, Coordinating PI: Novartis; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. All other authors have declared no conflicts of interest.