Prognostic Features of Immune Response in Colorectal Cancer

Colorectal cancer (CRC) is one of the most common cancers worldwide.Although
TNM staging is the most widely appliedmethod to classify the spread of CRC, the
prognosis may vary substantially evenbetween patients in the same stage. The
immune environment has been recognized as an important factor in the prognosis of CRC. Tumor-infiltrating lymphocytes seem to have great significance in suppressing tumor growth; in particular, thehigh intratumoral infiltration of CD3+ and CD8+ cytotoxic T lymphocytes and adjacent tertiary lymphoid structures, called the Crohn’s-like lymphoid reaction (CLR) in CRC, are associated with favorable prognosis in many different malignant tumors, including CRC.
As a sign of striving for immune evasion in a hostile microenvironment, some
tumors express high levels of inhibitory checkpoint proteins including PD-1
(programmed cell death protein-1) and PD-L1 (programmed cell death ligand-1).
Consequently, new therapeutic approaches through cancer immunotherapy with checkpoint blockade have proven effective in numerous cancers, including mismatch repair (MMR)-deficient CRC. This dissertation aimed to clarify the prognostic utility of immunohistochemical analysis of the tumor immune environment in CRC.
In Study I, tumor-infiltrating CD3+ and CD8+ Tlymphocytes as a combined
immune cell score proved to be an independent prognostic factor for survival in a cohort of 510 colon cancer patients regardless of tumormismatch repair (MMR)
status or TNM stage.
In the second study, 94 MMR-deficient CRCs, together with 100 age-and-stage
matched MMR-proficient tumors and 48 Lynch syndrome-associated tumors, were analyzed and compared. The combination of CD3+, CD8+, and PD-1+ lymphocyte densities and the PD-L1 expression rate of intratumoral immune cells into a single score called an “immunoprofile” proved to be an independent and more accurate prognostic tool than all the components separately.
In Study III, 346 rectal cancers [95 with short-course radiotherapy (SRT), 97 with
long-course chemoradiotherapy (CRT), and 154 without preoperative treatments] were evaluated from whole-slide samples of surgical specimens for histopathologic features, including CLR density. T lymphocyte densities were diminished after SRT, but CLRs were scarcer after CRT. The T cell proximity score and CLR density were prognostic for rectal cancer without preoperative treatments and could be combined into an enhanced prognostic score (immune grade). In the irradiated tumors, the impact of T cell infiltration was insufficient alone, although CLR density remained prognostic. However, their combination improved the performance of both.
In the fourth study, to evaluate the potential for PD-1 blockade therapy in a large population-based cohort of 1343 CRC patients, we analyzed the tumor
microenvironment and reviewed the clinical data and actualized treatment modalities of all MMR-deficient CRCs in Central Finland Central Hospital during 2000–2015. A total of 171 MMR-deficient CRC patients were identified, with 35 of these having a metastasized disease. As MMR-deficient CRC patients were generally older with significant comorbidities, only a limitednumber of patients with metastatic disease ended up undergoing oncological treatments. Many metastatic tumors presented features that could impair the response to PD-1 blockade therapy.
In conclusion, analysis of the tumor microenvironment can be helpful inthe
prognostic evaluation of CRC despite widely variable clinicopathological tumor
features or different preoperative treatment modalities.