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HLA Mismatch in Transplant Organs Tied to Lower Skin Ca Risk

HLA antigen mismatch appears to be associated with reduced skin cancer risk in heart and lung transplant recipients, a secondary analysis of the Transplant Skin Cancer Network (TSCN), study suggests.

In the study of over 10,000 organ transplant recipients, a 7% to 8% reduction in skin cancer risk was observed for each additional mismatched allele (adjusted HR 0.93, 95% CI 0.87-0.99, P=0.01), according to Sarah Arron, MD, of University of California San Francisco, and colleagues.

With almost 60,000 years of follow-up, the protective effect of HLA antigen mismatch — as defined in the 2016 Organ Procurement and Transplantation Network guidelines — was statistically significant for both lung (adjusted HR 0.70, 95% CI 0.56-0.87, P=0.001) and heart transplant recipients (adjusted HR, 0.75, 95% CI 0.60-0.93, P=0.008), traditionally the most immunosuppressed transplant population.

“These results suggest that chronic exposure to mismatched alloantigens may stimulate tumor surveillance mechanisms in solid-organ transplant recipients that protect against the development of skin cancer,” the authors wrote in JAMA Dermatology.

But the effect was not detected for liver, kidney, or pancreas transplant recipients.

“The HLA-DR mismatch seemed to play the strongest role,” Arron’s group wrote. “Internists and dermatologists who treat organ transplant recipients should be aware that the risk of skin cancer may be higher in patients who underwent thoracic transplant and received a well-matched organ.”

After adjustment for age, sex, race/ethnicity, thoracic organ transplant, year of transplant, and pretransplant history of skin cancer, the reduced risk for developing any skin cancer was statistically significant for HLA-DR mismatch (adjusted HR 0.85, 95% CI 0.74-0.97, P=0.01), but not for HLA-A or HLA-B mismatch.

“In the U.S., no effort is made to match recipients and donors of heart or lung transplants for HLA antigen, but kidney donors are selected to some degree for compatibility at HLA-DR,” noted Michael Cecka, PhD, of the David Geffen School of Medicine in Los Angeles, who was not involved in the study.

“The finding that there is no effect for kidney, but there is for heart and lung is therefore suspicious,” he told MedPage Today.

The rate of skin cancer was numerically higher among kidney transplant recipients with no HLA antigen mismatch, but the outcome was not statistically significant (14.5% vs 11.0% in those with one or more, P=0.13).

“In general, cancers are less common among HLA matched recipients because they get lower cumulative immunosuppression. In this study, I would wonder whether other factors are at work related to the distribution of more common HLA types in certain ethnic groups,” elaborated Cecka. “For example, HLA matches in random pairings would occur more frequently in patients of Northern European ancestry.”

The original findings from the multi-center TSCN study found that skin cancer occurred at a rate of 1,408 per 100,000 person-years after transplant, with some cancers more common than others:

  • Squamous cell carcinoma: 1,328 per 100,000 person-years
  • Melanoma: 122 per 100,000 person-years
  • Merkel cell carcinoma: 4 per 100,000 person-years

Compared with the general population, a recent study found that the risk of squamous cell carcinoma is increased 65-fold and melanoma 3-fold for solid-organ transplant recipients.

Conducted from 2016 to 2017, the TSCN study included 10,649 patients (6,776 men), with an average age of 51 years who received a primary transplant from 2003 to 2008.

In the current analysis, the adjusted HRs for squamous cell carcinoma and melanoma were similar to those for any skin cancer, however, due to the smaller number of melanoma diagnoses, the risk did not reach statistical significance.

Effective immunosuppression following transplant of solid-organs is a double-edged sword, in that it reduces the risk of graft rejection but appears to increase the risk of cancer, Arron’s group explained, and fewer mismatches typically help improve graft survival and rejection rates.

The authors concluded that follow-up studies should focus on determining how the burden of immunosuppression affects the association between the degree of HLA antigen mismatch and skin cancer risk, as well as the molecular mechanisms that explain the protective effect of HLA antigen mismatch.

Study limitations acknowledged by the group included selection bias introduced by use of patients from academic transplant centers, in that, compared with all transplant patients in the U.S., a larger proportion of these participants were older, white, and recipients of a thoracic transplant.

This work was supported in part by the Melanoma Research Foundation. The Transplant Skin Cancer Network was funded by the American Academy of Dermatology and by Galderma.

The authors reported no conflicts of interest.