Year: 2026
Type: conference-abstract
Abstract: Background Colorectal cancer (CRC) has the third highest incidence and the second highest mortality rate. 1 In patients with CRC, sensitivity to immune checkpoint blockers (ICB) is predominantly dictated by the presence of mismatch repair deficiency (dMMR) and/or high microsatellite instability (MSI-H) status.2 Uncovering actionable immune evasion pathways and immunotherapy targets for most CRCs lacking dMMR/MSI-H is a major unmet need. Local activation of IL-12 signaling in the tumor microenvironment (TME) drives prominent immunostimulatory and anti-tumor effect in pre-clinical models and early clinical trials.3 4 Understanding the expression, distribution and biological significance of the IL-12 pathway in human CRC could be used to support optimal therapeutic developments.Methods We established multiplexed quantitative immunofluorescence (mQIF) panels to measure and spatially map the IL-12 pathway (DAPI/CK/IL12Rβ1/pSTAT4/CD8), tumor-infiltrating lymphocytes (TILs; DAPI/CK/CD8/CD4/CD20), tumor associated macrophages (TAMs; DAPI/CK/CD14/CD68/CD206) and dendritic cells (DCs; DAPI/CK/CD11c/XCR1/HLADR) in consecutive sections of primary tumors from two clinically/molecularly annotated independent CRC cohorts represented in tissue microarrays. A third cohort comprising paired CRC and adjacent non-tumor colonic mucosa was also included. The tumors were also studied using whole exome DNA sequencing.Results IL12Rβ1 expression was identified in >95% of tumors (mean 1045 ± 200.8 cell/mm 2), with membranous staining pattern and continuous distribution across cases. No consistent association between IL-12 pathway markers and major clinicopathologic variables or MMR/MSI status was found. Elevated IL12Rβ1 levels were associated with increased CD8+ TILs and longer 3-year progression-free survival. Notably, 11.1-18.1% of CRCs displayed IL12Rβ1 expression in cancer cells, which was associated with increased pSTAT4 levels. As expected, the top mutated genes included APC, TP53, KRAS, FBXW7, PTEN and SMAD4. Expression of the IL-12 pathway markers was comparable across tumors with different oncogenic mutations. The presence of deleterious APC mutations was associated with distinct TAM subpopulations and high tumor mutational burden was associated with increased DCs subsets. The IL-12 pathway marker levels were comparable in tumor tissue and adjacent non-tumor colonic mucosa.Conclusions IL-12 pathway activation occurs in most primary CRCs and is associated with a favorable TME composition, independent of genomic alterations. IL12Rβ1 is expressed in malignant cells from ~14% of primary CRCs and associated increased STAT4 signaling, suggesting a biological role in cancer. These results can support optimal development of IL-12 directed therapies and patient selection strategies.Acknowledgements YPTS and YCGA cores (Yale), Pablo Vieyra-Garcia and Antonia Geyer (Boehringer Ingelheim).References Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023;72:338–344.Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413.Brunda MJ, Luistro L, Warrier RR, Wright RB, Hubbard BR, Murphy M, et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med. 1993;178:1223–1230.Atkins MB, Robertson MJ, Gordon M, Lotze MT, DeCoste M, DuBois JS, et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res. 1997;3:409–417.
Institutions: Yale University, Boehringer Ingelheim (United States)
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225145503