Favorable Immune Signature in CLL Patients, Defined By Antigen-Specific T-Cell Responses, Might Prevent Secondary Skin Cancers

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. The course of disease predisposes patients to the development of secondary malignancies, which might be due to a generalized immunosuppression induced by the disease and/or the therapies used for treatment. Skin cancer, including melanoma, is the most common secondary malignancy reported in these patients.

In a recent study we reported on spontaneous memory T cell responses against CLL-associated antigens defined by HLA ligandome analysis in CLL patients. Moreover, retrospective analysis suggests a significant survival benefit for CLL patients showing immune reactions to more than one of the tested antigens (Kowalewski et. al., PNAS 2015).

Here we analyzed our CLL patient cohort for the incidence of secondary malignancies, and in particular for skin cancers. A total of 15 CLL-associated HLA-peptides (6 A*02, 3 A*03, 6 B*07) were implemented for stimulation of HLA-matched PBMC obtained from CLL patients. 45 CLL patients (Binet A n=15, Binet B, n=15, Binet C n=15, median age, 33.3% (15/45) with prior CLL specific therapy) were analyzed for antigen-specific memory T-cell responses in IFNγ-ELISPOT assays. 13 patients (28.9%, response cohort) showed specific T cell response against > 1 antigen, while 32 patients (71.1%, negative cohort) showed none or only one immune response. The median age was 71 in the response cohort and 73 in the negative cohort. 40.0% (6/15) of CLL patients with Binet stage A and 33.3% (5/15) with stage B were classified as responders whereas only 13.3% (2/15) of patients with stage C showed  >1 immune responses. Of the included CLL patients with prior therapy only one patient (8%) showed > 1 immune responses. In the analyzed CLL patient cohort 7 skin cancers (melanoma: n=2, squamous cell carcinoma: n=2, basal cell carcinoma: n=3), 3 precancerous skin lesions and 9 other secondary malignancies including renal cell carcinoma (n=2), colon (n=3), breast (n=2) and prostate cancer (n=2) were observed. In the negative cohort 34.4% (11/32) of the patients developed a secondary malignancy, while only 15.4% (2/13) in the immune response cohort presented with secondary neoplasms. Strikingly all skin cancers and precancerous skin lesions were observed in the non-immune responder cohort. Furthermore multiple secondary malignancies (e.g. squamous cell carcinoma and colon cancer) were only observed in the cohort that showed no immune response.

Taken together our data suggest that a favorable immune signature in CLL patients, i.e. the ability to mount T-cell responses against CLL-associated antigens not only is associated with improved overall survival but also might protect these patients from the development of secondary skin cancers.