Spontaneous regression of human melanoma/nonmelanoma skin cancer: Association with infiltrating CD4⁺ T cells

Abstract

Spontaneous regression occurs in some human malignant melanomas and basal cell carcinomas (BCCs). We have compared the cellular infiltrate in regressing and nonregressing tumors in order to analyze the mechanism by which regression occurs. Regressing primary melanomas and BCCs were infiltrated with a larger number of CD4+, but not CD8+, T lymphocytes than were seen in nonregressing tumors. The number of interleukin 2 receptor-positive (early activation marker) but not transferrin receptor-positive (intermediate activation marker) T cells was increased, indicating that the infiltrating T cells were activated. Large numbers of Langerhans cells, macrophages, and other class II major histocompatibility complex (MHC)-expressing cells were present but were not increased in the regressing tumors. There were no detectable B lymphocytes, and the regressing tumor cells displayed levels of HLA-DR expression similar to those of the nonregressing tumors. Comparison of squamous cell carcinoma (SCCs) with keratoacanthomas (KAs), which are likely to be a spontaneously regressing form of SCC, also showed increased infiltration of activated CD4+, but not CD8+, T cells within the KA. A murine ultraviolet (UV)-induced squamous tumor that spontaneously regresses when transplanted into immunocompetent syngeneic mice was also infiltrated with increased numbers of activated CD4+, but not CD8+, T cells prior to and during rejection. These results indicate that spontaneous regression of human skin tumors is likely to be immunologically mediated, and that CD4+ T lymphocytes seem to mediate this regression.

Comparison of Oncostatin M Expression in Keratoacanthoma and Squamous Cell Carcinoma

“…The frequent presence of inflammatory cell infiltrates associated with KAs suggests a role for an immunologic host response in confining local growth, preventing distant metastasis, and inducing regression. Supporting this supposition are numerous studies demonstrating an increase of activated intratumoral CD4-positive T cells (34,35), fewer numbers of eosinophils (36), and increased Langerhans' cells (37) in KA compared with SCC, and a high incidence of KAs in patients who experience immunosuppression (20,38,39). In addition, KAs can exhibit expression of human leukocyte antigen DR (40).…”

CXC Chemokine Ligand 12 (Stromal Cell-Derived Factor 1α) and CXCR4-Dependent Migration of CTLs toward Melanoma Cells in Organotypic Culture

“…Thus, infiltration of melanoma lesions with T lymphocytes is an independent and favorable prognostic biomarker (45)(46)(47)(48), and CXCL12 expression by tumor cells of primary lesions as assessed by immunohistochemistry should be explored for its association with prognosis. …”

Preferential involvement of CX chemokine receptor 4 and CX chemokine ligand 12 in T-Cell migration toward melanoma cells

“…Infiltration of melanoma lesions with T lymphocytes is a favorable prognostic biomarker, [40][41][42][43] and CXCL12 expression by tumor cells of primary lesions may also have prognostic value. Furthermore, the favorable prognosis associated with CXCR3 and CCR4 expression by T lymphocytes of melanoma patients 44 points to the need for rigorous investigation of CXCR4 as a potential prognostic marker in these patients.…”