Immune Overdrive Puts Some Colorectal Cancer Patients at Risk for Poor Outcomes

By Marilynn Larkin

October 08, 2019

NEW YORK (Reuters Health) - Immune cell infiltration of tumors is usually associated with favorable outcomes, but sometimes in colorectal cancer (CRC) the opposite is true, researchers say. They caution that Immunoscore, developed to predict CRC recurrence, may incorrectly classify high-risk patients as low risk.

"The most important take-home for clinicians is that immune cell (including CD8 T) infiltration is not always a good thing in colorectal cancers," senior author Dr. Peter Lee of City of Hope in Duarte, California told Reuters Health by email. "This is particularly relevant with the push for incorporating the Immunoscore into clinical practice."

"The basis for 'immune overdrive' in some patients is unclear at this point and is the subject of our ongoing research," he said. "Patient factors such as genetic background may come into play. For colorectal tumors, microbes within the GI tract (microbiome) may also be factors."

Dr. Lee and colleagues note, "The prognostic value of immune cell infiltration within the tumor microenvironment has been extensively investigated via histological and genomic approaches. Based on the positive prognostic value of T cell infiltration, Immunoscore has been developed and validated for predicting risk of recurrence for CRC. Also, association between a consensus T helper 1 (Th-1) immune response and favorable clinical outcomes has been observed across multiple cancer types."

For the current study, the researchers reanalyzed public genomic data sets from The Cancer Genome Atlas and NCBI Gene Expression Omnibus and performed multispectral immunohistochemistry on a cohort of colorectal tumors.

As reported online September 16 in the Journal of Clinical Investigation, they identified and characterized a risk group, representing approximately 10% of CRC patients, with high intratumoral CD8+ T cell infiltration, but poor prognosis.

The tumors included both microsatellite instable and stable phenotypes, and had a high density of tumor-associated macrophages that expressed CD274 (programmed death-ligand 1), TGF-beta activation, and an immune overdrive signature characterized by the overexpression of immune response and checkpoint genes.

"It is important to note that our analysis does not contradict - but rather extends - the Immunoscore," the authors note. "The majority of CRC tumors with high CD8+ T cell infiltration still have favorable outcomes. However, our findings reveal that CRC tumors with concurrent high CD274 gene expression may be mislabeled as indicating good prognosis by simply following the Immunoscore classification, which is based solely on CD3 and CD8."

"As such," they say, "our results illustrate that not all CRC tumors with high T cell infiltration have good clinical outcome, and further refinement on Immunoscore as a prognostic marker can be made by including the CD8/CD274 signature."

Dr. Lee said, "Our approach is applicable to other cancers, and we are currently investigating to see if the immune overdrive state also occurs in other cancer types."

Lead author Dr. Marwan Fakih, also of City of Hope, added in the same email, "The challenge at this time is to develop a validated clinical assay that can be used to define this subgroup of patients in the clinic. Prospectively conducted clinical trials may shed additional light on the value of immunotherapy in this subgroup of patients."

Dr. Paul Oberstein, director of gastrointestinal medical oncology at the Perlmutter Cancer Center at NYU Langone in New York City, commented by email, "These findings are plausible and not entirely surprising."

"We know that patients with many mutations in their tumors (MSI-high colon cancer patients) receive substantial benefit from immunotherapy, but that this therapy does not work for all patients," he told Reuters Health. "It is possible that this (finding) will eventually explain some of that variability."

"It is very important to evaluate these studies in larger sets of patients, as this may reveal specifically which immune components are good and which are bad, and thus help stratify patients," he noted. "It is not known how treatment with either chemotherapy or immunotherapy interacts with these immune changes and this needs to be tested in ongoing, larger studies."

"Additionally, the study included a very small number of patients with advanced - i.e., metastatic - disease and it would be very important to know if the immune infiltrates are similar in these patients," he said.

"Finally, further work is needed to understand why some tumors are different than others," he added. "Is this due to changes in the tumor genes or the person with the tumor, and does diet, exercise, microbiome, or other environmental cause impact this result?"

In a statement provided to Reuters Health, Jerome Galon, Director of Integrative Cancer Immunology INSERM laboratory and co-founder of Immunoscore manufacturer HalioDx, wrote, "We see the work of Marwan Fakih et al. as of high importance. It confirms the key role of the T cell anti-tumor response in driving the development of colorectal tumors…. The results…(are) in line with our understanding of the immune modulation induced by cancer cells, validate the importance of measuring the T cell infiltration and evidence the complexity of the immune response to tumors but do not support a direct comparison or any conclusions on the performance of Immunoscore compared to a single gene expression measurement or to the CD8 and CD274 evaluation."


J Clin Invest 2019.