Regulatory (FoxP3+) T-cell tumor infiltration is a favorable prognostic factor in advanced colon cancer patients undergoing chemo or chemoimmunotherapy

Abstract

Antitumor immune response and chemotherapy-induced immunomodulation in colon cancer patients represented the rationale to design new strategies, like GOLFIG chemoimmunotherapy (gemcitabine, oxaliplatin, 5-fluorouracil/folinic acid, granulocyte macrophage colony-stimulating factor, and aldesleukine), that resulted a safe and very active regimen. Antitumor activity and immunity feedback to GOLFIG were strictly correlated with the best outcome observed in patients with autoimmunity signs, increase of central memory T cells, and decrease of regulatory T cells (Treg) in the peripheral blood. We thus investigated a potential correlation between the Treg tumor infiltration at diagnosis and the clinical outcome in a current randomized phase 3 trial aimed to compare the GOLFIG regimen with the standard FOLFOX chemotherapy (GOLFIG-2). An immunohistochemistry study was carried out to quantify the infiltration of Treg/FoxP3+ T lymphocytes in tumor samples of 57 patients enrolled in the GOLFIG-2 trial. Treg tumor infiltration scores were correlated with overall survival, treatment-relative survival, and progression-free survival (PFS). Higher Treg tumor infiltration scores were associated with a better prognosis in the whole series (Treg high score vs. low score: overall survival=mean 43.2 mo vs. 28.6 mo, P=0.0005) and a better outcome after treatment (Treg high score vs. low score: PFS=mean 15.8 mo vs. 8.8 mo, P=0.0009; treatment-relative survival=mean 23.1 mo vs. 18.2 mo, P=0.004). PFS was significantly longer in GOLFIG high versus all other subgroups (mean 18.1 mo vs. 9.9 mo, P=0.01). Our results suggest that a higher FoxP3+ T-lymphocyte tumor infiltration score is a favorable prognostic factor in colon cancer patients undergoing chemo or chemoimmunotherapy.

FIGURE 1.

Immunohistochemistry scores of T lymphocytes expressing FoxP3; panels A represents score 1; B, score 2; C, score 3;D, score 4; and E, score 5 (original magnification × 200).

FIGURE 2.

Actuarial Kaplan-Meyer survival curves of 57 colon cancer patients undergone FOLFOX or GOLFIG treatment whose tumor was immunohistochemically scored for T_reg infiltration. Panels compare overall survival (A), relative overall survival (from trial enrolment to death; B), and progression-free survival (C) with infiltrating lymphocytes expressing FoxP3.

FIGURE 3.

Regression curves (solid line) (with 95% confidence interval) (dotted line) according to the number of tumor-infiltrating lymphocytes positive for the expression of FoxP3. Panels compare overall survival (A), relative overall survival (from trial enrolment to death; B), and progression-free survival (C) with the actual number of tumor-infiltrating lymphocytes positive for the expression of FoxP3. Panels compare overall survival (D), relative overall survival (E), and progression-free survival (F) with the actual number of tumor-infiltrating lymphocytes positive for the expression of FoxP3 in patients with (●) or without events (○).