Immune phenotype predicts risk for posttransplantation squamous cell carcinoma

Abstract

Cutaneous squamous cell cancer (SCC) affects up to 30% of kidney transplant recipients (KTRs) within 10 years of transplantation. There are no reliable clinical tests that predict those who will develop multiple skin cancers. High numbers of regulatory T cells associate with poor prognosis for patients with cancer in the general population, suggesting their potential as a predictive marker of cutaneous SCC in KTRs. We matched KTRs with (n = 65) and without (n = 51) cutaneous SCC for gender, age, and duration of immunosuppression and assessed several risk factors for incident SCC during a median follow-up of 340 days. Greater than 35 peripheral FOXP3(+)CD4(+)CD127(low) regulatory T cells/microl, <100 natural killer cells/microl, and previous SCC each significantly associated with increased risk for new cutaneous SCC development (hazard ratio [HR] 2.48 [95% confidence interval (CI) 1.04 to 5.98], HR 5.6 [95% CI 1.31 to 24], and HR 1.33 [95% CI 1.15 to 1.53], respectively). In addition, the ratio of CD8/FOXP3 expression was significantly lower in cutaneous SCC excised from KTRs (n = 25) compared with matched SCC from non-KTRs (n = 25) and associated with development of new cutaneous SCCs. In summary, monitoring components of the immune system can predict development of cutaneous SCC among KTRs.

Figure 1.

Maximal proliferative response of peripheral blood leukocytes to PHA in healthy control subjects (n = 32), KTRs with SCC, and matched KTRs without SCC. Poor proliferative response, defined as a count of <10,000 cpm (10th centile of healthy control subjects), was more common in KTRs with a history of SCC (OR 3.7 [95% 1.5 to 9.8]; P = 0.004).

Figure 2.

Immunophenotype of infiltrating lymphocytes in cutaneous SCC is shown. (A and B) Paraffin-embedded tissue sections of cutaneous SCC were investigated by triple immunoenzymatic labeling for detection of CD56 (brown), CD8 (blue), and FOXP3 (pink) antigens (no counterstain). Within each tumor, two areas were identified: One showing intratumor lymphocyte infiltration (IT; A) and the second characterized by a peritumor infiltrate (PT; B). IT areas were composed mainly of FOXP3⁺ cells (pink), contrasting with the PT areas showing a predominance of CD8⁺ cells (blue).

Figure 3.

(A) Kaplan-Meier curve shows time to next SCC in 65 KTRs with a previous SCC. Top line represents KTRs with only one previous SCC; bottom line represents KTRs with more than two SCCs (HR 12.5 [95% CI 1.7 to 94.0]; P = 0.014). Tick marks represent censored observation for time of follow-up. (B) Kaplan-Meier curve of time to next tumor when KTRs are categorized as having >35 FOXP3⁺ cells/μl and <100 NK cells/μl. Bottom line represents those with high FOXP3⁺ cell number and low NK cell number (high-risk phenotype; n = 11); top line represents those with low FOXP3⁺ cell number and high NK cell number (HR 3.77 [95% CI 1.42 to 10.00]; P = 0.008 for high-risk phenotype). (C) Kaplan-Meier curve combining high-risk phenotype and single or multiple previous SCCs. Bottom line represents KTRs (n = 8) with high-risk phenotype and multiple previous SCCs (HR 6.13 [95% CI 2.30 to 16.00]; P < 0.001 for new SCC development).