Immune checkpoints (ICs) are molecules that modulate the duration and amplitude of physiological immune function, playing important roles in maintaining immune homeostasis (1). Immune checkpoint inhibitors (ICIs) are antibodies that target certain immune checkpoints (ICs), such as programmed death 1 (PD-1), its ligand (PD-L1), or cytotoxic T-lymphocyte antigen-4 (CTLA-4) (1, 2). ICIs have emerged as a powerful new tool for various types of cancers, namely, lymphoma, melanoma, lung cancer, renal cell carcinoma, urothelial carcinoma, etc. The indications of ICIs are currently increasing (1–5).

As these ICs are crucial for immunological self-tolerance, such therapies can trigger autoimmune adverse effects, affecting a number of organs (2, 6). Endocrinopathies are among the most common complications, including thyroid dysfunction, hypophysitis, and more rarely diabetes mellitus (DM) and primary adrenal insufficiency (6). The time of onset of endocrinopathies presents a great range (weeks to months after the initial dose) (7, 8). Furthermore, the severity of endocrinopathies presents a great range and grading systems are used in the clinical practice (1, 9). Combination of ICIs appears to increase the risk of endocrine complications (2, 3).

It has been hypothesized that autoimmune complications or immune-related adverse events (irAEs) after ICIs may be a positive predictor of immunotherapy response (10). Particularly, several studies and a recent meta-analysis provided evidence that progression-free survival (PFS) and overall survival (OS) are longer in patients with development of autoimmune disorders in general and of endocrinopathies specifically (11–13). A recent study provided evidenced that the development of autoimmune complications was associated with improved survival in patients with advanced (stage III/IV) NSCLC treated with anti-PD-L1 agents (12). Such autoimmune complications, including endocrine ones, may represent bystander effects from activated T lymphocytes and despite undesirable symptoms can correlate with favorable disease outcomes. This phenomenon is known in the literature as “beneficial autoimmunity” (10, 14).

However, evidence so far is scarce and the exact mechanisms remain elusive. Moreover, not all studies have provided similar results and the topic remains quite controversial (13). As this hypothesis needs further investigation, we aimed to investigate the association of endocrine complications after ICI immunotherapy with PFS and OS in a large single-center oncological cohort.

The aim of this study was to investigate the association of endocrine complications after ICI immunotherapy with PFS and OS in a large cohort of oncological patients. We observed that 19.4% of participants presented endocrinopathies in total. Oncological patients with an endocrine complication after ICIs had longer mPFS compared with those without endocrine complication. Similarly, median OS was statistically significantly lower in the patients’ group without endocrine complication. These results retained significance even after multivariate analysis, including gender, stage of cancer, type of immunotherapy, and type of cancer.

The results of our study are in accordance with other recent findings, proposing that autoimmune complications after ICIs may be a positive predictor of therapy response. A recent large meta-analysis (13) included 30 (15–44) studies with 4,971 individuals and provided evidence that patients with autoimmune complications after ICIs experienced both an OS benefit and a PFS benefit compared with patients who did not develop such complications [OS: hazard ratio (HR) 0.54, 95% CI 0.45–0.65; p < 0.001; PFS: HR 0.52, 95% CI 0.44–0.61, p < 0.001). Specific analysis regarding endocrine complications yielded similar results (OS: HR 0.52, 95% CI, 0.44–0.62, p < 0.001). The same was found for dermatological (OS: HR 0.45, 95% CI 0.35–0.59, p < 0.001) and low-grade irAEs (OS: HR 0.57, 95% CI 0.43–0.75; p < 0.001) (13). Another later multicenter cohort study confirmed that the development of multisystem immune-related adverse events was associated with improved survival in patients with advanced (stage III/IV) NSCLC treated with anti-PD-L1 agents (12).

We need to note that a definite conclusion on the topic has not been drawn yet, as several single studies have provided negative or contradictory results (34–46). However, recent and increasing evidence, including our findings, suggests that such complications can be a positive predictor of immunotherapy response, despite the undesirable symptoms. The exact mechanisms of the association between autoimmune complications and survival benefits are not completely clear. Such adverse events are thought to represent bystander effects from activated T lymphocytes. An immune response against both the tumor and healthy cells or tissues seems to take place, probably through antigen mimicry procedures. The humoral immunity dysregulation has been additively proposed as a possible explanation for the phenomenon. For example, the PD-1 signaling pathway modulates B cell activation in both T-cell-dependent and -independent pathways (10, 13).

There is a term in the literature known as “beneficial autoimmunity.” Importantly, the nature of “beneficial autoimmunity” is substantially influenced by the type of cancer treated. For example, the induction of vitiligo in the case of melanoma is a good prognostic sign, while the repigmentation is associated with progression. In contrast, the presentation of pneumonitis in a patient with lung cancer would indicate poor prognosis. The difference reflects the fact that autoimmune responses that lead to the eradication of non-essential cells, such as melanocytes, are affordable to the body whereas damage of essential tissues, such as respiratory cells in the lung, is not (10). This is in accordance with the data from the recent meta-analysis that confirmed the association of endocrine, dermatological, and low-grade autoimmune complications with favorable outcomes (13). Of note, thyroid dysfunction is considered the most frequent ICI complication, irrespective of the location of the primary tumor (2, 6, 10, 13). Similarly, in our study most patients presented with thyroid dysfunction. Specifically, 66 (18.8%) had thyroid dysfunction, 1 patient presented hypophysitis (0.3%), and 1 patient had a combination of thyroid dysfunction and hypophysitis (0.3%).

In our study, most of the patients received immunotherapy with anti-PD1 agents (262, 74.6%) and the rest with anti-PD-L1 agents (89, 25.4%). Interestingly, the recent meta-analysis (13) showed that the association between autoimmune complication development and a favorable benefit on survival was significant in those patients undergoing treatment with anti-PD1 agents (OS: HR 0.51, 95% CI, 0.42–0.62, p < 0.001), but not with CTLA-4 inhibitors (OS: HR 0.89, 95% CI, 0.49–1.61, p = 0.706). In the meta-analysis, 26 studies adopted anti-PD-1 agents, 3 anti-CTLA-4 agents, and 1 anti-PD-1/PD-L1 agents (13). We need to take into consideration the lower numbers regarding CTLA-4 inhibitors; however, there may be a pathophysiological explanation too. Indeed, CTLA-4 inhibition activates T cells at an earlier stage of their development. Therefore, such an inhibition may directly disrupt central tolerance without affecting tumor immune response at the same time (1, 6, 13).

We found no statistically significant differences in mPFS of different cancer types, while the presence of endocrine complications was a positive predictor for longer mPFS in patients with renal cancer and bladder cancer, but not in patients with lung cancer, ovarian cancer, or other types of cancer. We need to note that numbers of the latter patients’ subgroups may be low to prove such an outcome for each different type of cancer. Indeed, several previous studies have shown favorable outcomes for patients with melanoma and lung cancer who developed various irAEs after immunotherapy with ICIs (12, 13, 15–17, 19–23, 25, 26).

The main strength of the study is the large number of participants. This is one of the largest cohorts in the literature. All patients come from the same academic unit, which implies another strength—that all participants were followed up by the same multidisciplinary team and with the same protocol. Numbers may be low for separate types of cancers, and this can be considered as a limitation. Moreover, data are retrospectively analyzed, however deriving from a prospectively collected cohort. Last but not least, a potential survivorship bias may exist for the development of irAEs.

In conclusion, this study provided evidence that oncological patients who present endocrine complications after ICI immunotherapy had longer mPFS and mOS compared with those without endocrine complication. These results retained significance even after multivariate analysis, including gender, stage of cancer, type of immunotherapy, and type of cancer. Therefore, physicians dealing with such patients should be aware that endocrine complications after ICIs may be a positive predictor of immunotherapy response and a prognostic factor of longer PFS and OS.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Alexandra Hospital Ethics Committee. The patients/participants provided their written informed consent to participate in this study.

SP designed the protocol and wrote the manuscript. ML participated in the collection of the data and performed the statistical analysis. EE-P participated in the collection of the data. KS participated in the collection of the data. CM participated in the collection of the data. KK participated in the collection of the data. FZ participated in the collection of the data and revised the manuscript. TP participated in the collection of the data and revised the manuscript. M-AD designed the protocol and revised the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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