Immune signature reveals new therapeutic potential in colon cancer

From Dr. Jeroen Huyghe and the Peters Lab, Public Health Sciences Division

The anti-tumor immune response plays a critical role in regulating tumor progression and patient survival. Immunotherapy strategies harness this immune response to override immune checkpoints and ramp up the body’s ability to eliminate cancer cells, which have “transformed cancer care for multiple solid cancer types,” notes Dr. Jeroen Huyghe, a senior staff scientist in Dr. Ulrike (Riki) Peters’ lab in the Public Health Sciences Division at Fred Hutch. Huyghe goes on to explain, “In colorectal cancer, only a small subset of patients with tumors deficient in mismatch repair or high in microsatellite instability have demonstrated clinical benefit from immunotherapy. However, the vast majority of colorectal cancer patients are mismatch repair proficient (non-hypermutated) or microsatellite-stable.” Finding a way to make these cancers more immunogenic and compatible with immunotherapy is of great interest. “Studying the tumor immune microenvironment profile in these patients’ tumors together with genomic correlates and survival outcomes may provide new leads.”

One way to evaluate the tumor-fighting-ability of a patient’s immune system and tumor susceptibility to immune checkpoint inhibitors is to characterize the patient’s T cell-inflamed gene expression profile (GEP)- “an integrative biomarker related to interferon-gamma (IFNγ) and other immune activities like antigen presentation, chemokine expression, cytolytic activity, and adaptive immune resistance,” explains Hang Yin, a graduate student in the Peters Lab. In their recent Cancer Medicine study led by Yin and Huyghe, the researchers “aimed to evaluate the prognostic value of the T cell-inflamed GEP in colon cancer patients by examining its association with colorectal cancer-specific survival,” Yin noted. Here, they found that “the T-cell inflamed GEP gives a more comprehensive picture of anti-tumor immune activity in colorectal cancer, which shows more patients have potential to benefit from immune checkpoint inhibitor treatment,” Yin exclaimed.

Kaplan–Meier plot of the association between colorectal cancer‐specific survival and dichotomized T cell‐inflamed gene expression profile (GEP) among (A) all patients and (B) non‐hypermutated and microsatellite‐stable patients.
Kaplan–Meier plot of the association between colorectal cancer‐specific survival and dichotomized T cell‐inflamed gene expression profile (GEP) among (A) all patients and (B) non‐hypermutated and microsatellite‐stable patients. Image taken provided by Yin Hang.

To understand whether the T cell-inflamed gene expression profile could be used as a prognostic tool for colon cancer patients, the researchers utilized tumor samples collected from 80 colorectal cancer patients in the Seattle Colon Cancer Family Registry. Yin et al. scored each patient based on high or low score of the T cell-inflamed GEP  in addition to identifying somatic mutations present in these tumors. The researchers then used statistical methods to evaluate correlations between the data sets to determine if immune gene expression and somatic mutation profiles correlated with patient survival. They found that patients with “a high T cell-inflamed GEP score had more favorable colorectal cancer-specific survival,” Yin stated. They also discovered that a high GEP score was associated with greater microsatellite instability and overall tumor mutation burden. However excitingly, the T cell-inflamed GEP prognostic was also found to be “independent of hypermutation, microsatellite instability, and cancer stage, and it remained prognostic among patients with non-hypermutated and microsatellite-stable phenotypes, the group that were thought to not respond to immunotherapy,” Yin explained. This finding was particularly important since this group “makes up the majority of sporadic colorectal cancer cases,” Huyghe added. He continued to explain that in these patients, “the tumor microenvironment displays huge variability in the degree of inflammation and that this inflammation is such a strong positive prognostic factor. This underscores that even within non-hypermutated and microsatellite-stable patients, the anti-tumor immune response is playing a very important role in cancer progression and likely, also the response to standard-of-care treatment that determines clinical outcome.” Furthermore, the researchers analyzed genes that were recurrently mutated across at least 10 patients, to ask if certain DNA mutations correlated with T cell-inflamed GEP score. Among these, Yin et al. found a negative correlation between T cell-inflamed score and mutations in tumor suppressor APC and a positive correlation between T cell-inflamed GEP and mutations in RYR1- a ryanodine receptor in which gain-of-function mutations may promote faster immune responses. The researchers also found a negative association between T cell-inflamed GEP and expression of several Wnt signaling genes and stem cell marker ITGA6, suggesting that these genes might play immune-inhibitory mechanisms and could be potential druggable targets.

Together, these data highlight that current determinants of colorectal cancer responsiveness to immune checkpoint inhibitors, such as using “a single biomarker like microsatellite instability, are insufficient at capturing immune responses,” Yin explained. Importantly, this study found that some patients with colorectal cancer deemed incompatible with immunotherapy, might actually respond well to it, highlighting the need to “further study patient stratification for immune checkpoint inhibitors and research new therapeutic strategies that harness the immune response within the subset of non-hypermutated/microsatellite-stable colorectal cancer patients,” Huyghe added. Furthermore, the researchers discovered several genes related to immune-inhibitory signals were inversely related to GEP score, which may yield tractable drug targets. Future work aims to extend this study to investigate “the T cell-inflamed GEP among colorectal cancer patients from African American, Alaska Native, Hispanic, and non-Hispanic White people in the Translational Research Program in Colorectal Cancer Disparities (TRPCD),” Yin explained. Yin added, that through examination of gene expression profiles and “other well-known molecular biomarkers, like consensus molecular subtypes, we aim to understand the biological factors underlying the substantial variation in mortality across race and ethnicity.”

This work was supported by the National Institutes of Health, the National Cancer Institute, Fred Hutch’s Immunotherapy Integrated Research Center and Juno Therapeutics.

Fred Hutch/University of Washington/Seattle Children's Cancer Consortium members Ulrike Peters, Amanda Phipps and Li Hsu contributed to this work.

Yin H, Harrison TA, Thomas SS, Sather CL, Koehne AL, Malen RC, Reedy AM, Wurscher MA, Hsu L, Phipps AI, Zaidi SHE, Newcomb PA, Peters U, Huyghe JR. T cell-inflamed gene expression profile is associated with favorable disease-specific survival in non-hypermutated microsatellite-stable colorectal cancer patients. Cancer Med. 2022 Nov 7. doi: 10.1002/cam4.5429. PMID: 36341526.