The immune microenvironment is a critical regulator of colorectal cancer (CRC) biology and is a clinically targetable tumor feature. However, much less is known about the immune microenvironment of polyps and the precursor lesions that give rise to CRC and how the immune response shapes neoplastic progression. We utilized multispectral immunofluorescence, digital imaging, and supervised machine learning to quantify T populations in more than 1,000 normal mucosa and precursor tissue specimens (all classified using 2019 WHO criteria), including adenomas and serrated lesions, from two U.S.-based large prospective cohort studies. Overall, precursors have a similar T cell density but a higher CD8:CD4 ratio than normal mucosa. CD3+CD4+ and CD3+CD8+ cell densities decrease in a proximal-distal anatomic gradient, and both populations are inversely correlated with precursor size. Serrated lesions, including hyperplastic polyps and sessile serrated lesions, have a higher intraepithelial CD3+CD8+ density than adenomas. While tubular adenomas have higher CD3+CD4+ densities than tubulovillous and villous adenomas, degree of dysplasia in adenomas does not correlate with T cell densities. In summary, numerous polyps and precursor features correlate with T cell densities and subtype composition, suggesting an important yet poorly characterized role for the immune response in regulating the earliest steps of colorectal neoplasia.
Colorectal cancers develop from polyps that are present in many people and are removed during colonoscopy to reduce the chance of progression to colorectal cancer. In colorectal cancer patients, the body’s immune system attempts to eradicate the cancer, and this process can be enhanced using FDA-approved therapies. However, we know very little about the immune response to colorectal polyps and whether different types of polyps with different risks of progression to colorectal cancer harbor different immune cells. We answered this question by collecting more than 1000 polyp and normal colon specimens from patients across the United States enrolled in two prospective research studies. We built a laboratory assay that identifies T lymphocytes, the key immune cells that drive anti-tumor immune responses and used artificial intelligence to count them in patient specimens. We found that the two major classes of polyps have different T lymphocyte profiles, that polyps in different parts of the colon have different T lymphocyte profiles, and that some polyps with a higher risk of progressing to colorectal cancer have fewer T lymphocytes that lower risk polyps. These results help us understand how the immune system might be modified to prevent polyp formation and progression to cancer.