Merkel Cell Carcinoma (MCC) is a rare primary cutaneous neuroendocrine carcinoma usually involving the sun-exposed skin of elderly individuals, but sometimes also the trunk and limbs (1). Immunosuppression, chronic ultraviolet (UV) exposure, and old age are known predisposing factors (2), and MMC incidence is rising in Western countries (3). Clinical presentation is a rapidly growing, painless, erythematous/violaceous nodule or plaque (4). MCC is an aggressive tumor, as synchronous nodal and/or systemic metastases are present in about one-third of cases (2). Merkel Cell Polyomavirus (MCPyV) seems to be the pathogenic factor for about 80% of MMCs in the northern hemisphere, as viral DNA was shown to be integrated within the tumor genome (1, 5). The genetic damage induced by UV radiation accounts for the pathogenesis of the MCPyV-negative MCCS, showing a high tumor mutational burden (TMB) and a UV mutational signature (6).

The Immune Checkpoint Inhibitors (ICIs), anti-PD-L1 avelumab and anti-PD-1 pembrolizumab, have been recently approved as first-line treatment in metastatic MCC, although only a minority of patients exhibit long-term response (7, 8). Response to ICI therapy did not correlate either with MCPyV or with UV mutational signature status (9). An association with PD-1/PD-L1 tumor tissue expression was found (9, 10), but current assays remain imperfect to predict which patient will benefit from immunotherapy (11). Thus, further predictors of response are needed.

Recently, the clinical, contrasting, observation of improved outcomes in obese patients following treatment with immune checkpoint blockade, known as the “obesity paradox”, has been studied across many types of tumors (12). Cancer patients with high body mass index (BMI) seem to respond better to ICI therapy when compared to those with normal BMI (13–17). Probably due to the rarity of this tumor, data on the relationship between BMI and response to ICI treatment among MMC patients are lacking. Although the mechanistic link between metabolic state and immunotherapy benefit was not clearly elucidated, clinical data linking excess adiposity to ICI response in MCC patients could give more insights into the complex immune-metabolic interactions, serving as both predictive and stratification factors in future clinical trials.

MCC is an uncommon and highly aggressive neuroendocrine neoplasm difficult to treat (4). Until some years ago the treatment of choice for advanced MCC has been chemotherapy, as well as in poorly differentiated neuroendocrine neoplasms, showing a median PFS of 3–4 months, median OS of less than 10 months, and significant toxicity (4, 18). The association between increased MCC incidence in the elderly and/or immunocompromised subjects and pathological immune dysfunction always suggested a significant role of the immune system in MCC development (19, 20).

Recently, immunotherapy has become the mainstay of treatment of metastatic disease, with durable responses in some cases (21). To date, three immune checkpoint inhibitors (avelumab, pembrolizumab and nivolumab) (7, 22, 23), and the combined nivolumab and ipilimumab (24) resulted to be active in the treatment of advanced MCC. Avelumab was the first approved anti-PD-L1 treatment for patients with metastatic MCC, based on efficacy and safety data observed in the JAVELIN Merkel 200 trial (22). However, as well as for other cancers, only around half of the patients with mMCC respond to the immune‐checkpoint blockade, and a substantial number of patients developed acquired resistance. Consequently, there is a clinical need for predictive factors of immunotherapy response, and understanding the underlying tumor immune escape mechanisms following the ICI treatment is urgently warranted (25).

Recent pan-cancer outcome analyses on patients with or without obesity treated with ICIs showed that presenting with a BMI of 30 or higher was associated with prolonged survival than having BMI less than 30. This study was performed across many cancer types, such as melanoma, NSCLC and SCLC, renal cell carcinoma, bladder cancer, breast cancer, gastric cancer, colorectal cancer, endometrial cancer, sarcoma, and others (12), and the final results were in agreement with some previous published studies that hypothesized the “paradoxical effects” of obesity on cancer immunotherapy across multiple tumor types.

To our knowledge and based on the best data available today, this is the first study that investigates the role of BMI in patients affected by Merkel Cell Carcinoma treated with checkpoint blockade immunotherapy. In our survival analyses, obese mMCC patients showed improved PFS following avelumab treatment than patients with overweight or normal weight. Multivariable Cox regression analyses confirmed these results.

This is consistent with the notion that obesity might lead to an immune aging effect, which could be particularly highlighted in elderly MCC patients. These patients seem to be often immunocompromised, not only for the physiological age-related immune senescence, but also for the frequent history of solid organ and/or hematological stem cell transplantation, and hematological malignancies, especially B cell chronic lymphocytic leukemia (20). Notably, obesity is often accompanied by a chronic low-grade systemic inflammation (26–28), stimulated by the production of the pro-inflammatory cytokines, which alters the microenvironment of expanded adipose tissue. Chronic inflammation can induce immunosuppression as a result of a T cells exhaustion by persistent antigenic stimulation, ultimately inducing dysfunction of the immune system in obese patients (28).

Thus, advanced age, a weakened immune system, and the potential obesity-associated “inflammaging” (28), are key factors that could impact the cancer immune responses in the context of immunotherapy treatment of mMCC patients.

Despite our results showed that most of obese mMCC patients were younger [9 out 12 patients <75 years old (75%) had BMI ≥ 30] than patients with normal weight or overweight, MCC is a tumor of elderly individuals, and the median age of these patients, stratified as younger, were 63 years. In agreement with the known causes of progressive disease or death during avelumab treatment, this result linking higher BMI and younger age was not influenced by clinical factors beyond the metastatic cancer diagnosis.

Although our study focuses on obesity and outcomes of ICI, we further observed a predictive value of platelet counts at baseline before immunotherapy. Interestingly, according to a growing body of evidence, a direct cross-talk between platelets and host immunity seemed to exist (29). Pre-clinical studies have suggested the contribution of platelets to systemic and local responses against cancers (30). Platelets lack a nucleus and DNA available for the transcription of new RNA molecules. However, they can sequester molecules, including RNA and protein transcripts, altering their spliced RNA profiles (31, 32). Specific splice events may be induced in response to signals released by tumor cells and the tumor microenvironment (33). Thus, the resulting “tumor-educated platelets (TEPs) represent dynamic biomolecules with a rich and highly variable repertoire of mRNA, transported from the tumor microenvironment forward multiple anatomic sites (30, 34).

Furthermore, tumor-associated thrombocytosis has been linked to poor clinical outcomes in several cancers, including pancreatic cancer, hepatocellular carcinoma, renal cell carcinoma or glioblastoma (15, 35–38), and it recently has been significantly associated with a poorer prognosis in lung cancer and melanoma patients receiving immunotherapy (39–41). Rachidi et al. (42) showed that platelets can suppress T-cell responses against tumors through the production and activation of immunosuppressive factors, including TGFβ, demonstrating how platelet-related TGFβ activation contributes dominantly to the immunosuppressive tumor microenvironment.

In our study population, we observed that mMCC patients with higher platelet counts assessed at baseline had improved PFS following first-line avelumab treatment. The multivariable model confirmed the independent prognostic value of this finding. The biological reason remains speculative. A possible explanation is that the higher immunosuppression associated with elevated basal platelets may lead to a greater effect of immune checkpoint inhibitors in reinvigorating the T-cell immune response against the tumor following avelumab treatment.

Limitations of our study include the small sample size due to the rarity of this cancer and the retrospective data analysis. On the other hand, all the patients studied were consecutively collected from our single referral Center, thus patients’ data, although retrospective, should be homogenous, limiting possible biases. In addition, BMI is not a perfect assessment of obesity because it cannot distinguish muscle from body fat (43). Accordingly, more specific body fat assessment methods should be used in future prospective studies on larger cohorts.

MCC has long been considered to be immunogenic cancer because it occurs more frequently and has a worse prognosis in immunosuppressed individuals. Despite the therapeutic impact of reinvigorating the antitumor immune response by immunotherapy, the clinical benefit of ICIs in mMCC is still limited to selected patients. From previous studies across many cancer types, we have learned that in metastatic patients treated with ICIs, obesity is often associated with better clinical outcomes. Our findings validate this concept also in mMCC patients following avelumab treatment, demonstrating a positive effect on PFS of a BMI > 30. The association between basal platelet count and PFS seemed to suggest that a cross-talk platelets-host immunity exists. It remains to be elucidated whether other clinical, immunological or biological factors not yet investigated, may have a further relevant impact on tumor response and clinical outcomes.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethical committee of the University-affiliated Hospital A.O.U.P. “Paolo Giaccone” (Palermo 1)(approval number 1122). The patients/participants provided their written informed consent to participate in this study.

The authors confirm contribution to the paper as follows: Study conception and design: LI, VB, AR, and GB. Data collection: AD, LA, LM, IL, RS, AB, TB, FL, MP, DG, IF, FT, AC, and AF. Analysis and interpretation of results: LI, AD, CB, EP, AP, VG, AGi, AGa and GB. Draft manuscript preparation: LI, AD, LM, AP, CB, EP, and GB. All authors contributed to the article and approved the submitted version.