ENDOCRINE SOCIETY
OXFORD
Immune Checkpoint Molecules in Adrenocortical Carcinoma: Hope for Immunotherapy
Enzo Lalli1 D
1Institut de Pharmacologie Moléculaire et Cellulaire CNRS UMR7275, Inserm U1323, Université Côte d’Azur, 05650 Valbonne, France Correspondence: E. Lalli, MD, Institut de Pharmacologie Moléculaire et Cellulaire, 660 route des Lucioles-Sophia Antipolis, 06560 Valbonne, France. Email: ninino@ipmc.cnrs.fr.
Escape from immune destruction is widely recognized as one hallmark of cancer. Immune checkpoint inhibitors, targeted at counteracting suppressive mechanisms that impair elimin- ation of cancer cells by the immune system, have revolutionized the therapy of many types of cancer. An essential condition for efficient destruction of cancer cells is that solid tumors are infil- trated with immune cells able to eliminate them.
Adrenocortical carcinomas (ACCs) as a group are among the immunologically “coldest” (immune cell-depleted) tumors. Several mechanisms may acccount for this finding: immuno- suppressive effects of glucocorticoids produced by the tumor, activation of the Wnt/ß-catenin signaling pathway causing im- mune exclusion, and presence of TP53 mutations associated with reduced chemokine secretion and natural killer cell activ- ity. This may explain the overall limited success obtained up to the present time by the use of immunotherapy in the treatment of patients with ACCs at an advanced stage (1). Nevertheless, not all ACCs are created equal: total leukocyte infiltration as well as the abundance of lymphocyte subsets in the tumor microenvironment greatly differs in the ACC subtype charac- terized by high steroid hormone production compared to tu- mors producing little or no steroids (2). Several studies have shown that immune parameters have a prognostic value in both children and adult ACC (3, 4), indicating that the immune response has indeed an important role in fighting against ACC growth and spread. However, a precise estimate of the expres- sion of immune checkpoint molecules in ACC is needed to as- sess the probability of success of immunotherapy. The study by Landwehr et al (5) fills this knowledge gap since it reports data about the expression of PD-1, PD-L1, and CTLA-4 in a large series (considered the rarity of this tumor type) of ACC and their correlation with clinical parameters and prognosis. The authors have shown that PD-1 and its ligand PD-L1 were ex- pressed in slightly less than 30% of cases, while CTLA-4 was expressed in more than 50% of samples. PD-1 expression was correlated with longer progression-free survival and with the number of tumor-infiltrating T cells. As the authors observed, in ACC, PD-1 expression may be a proxy for tumor- infiltrating cytotoxic CD8+ T cells targeting cancer antigens by high-afffinity T-cell receptors. These results are consistent with
studies in other cancer types (colorectal carcinoma, non-small cell lung cancer), where PD-1 expression is significantly corre- lated with a better clinical outcome, while in breast cancer it is associated with a worse prognosis. Those contrasting data may be related to different degrees of T-cell activation in those tumors. It is interesting to remark that in the study by Landwehr et al, no prognostic correlation was observed for PD-L1 expression, while a previous study performed in The Cancer Genome Atlas adrenocortical carcinoma cohort found high expression of this marker associated with longer post- operative survival (6). Methodological issues [study of protein expression by immunohistochemistry in (5), mRNA analysis in (6)] and different cutoffs used may, at least in part, account for those discrepancies. Overall, the study by Landwehr et al is en- couraging about the possibility of relieving T-cell inhibition by immunotherapy in a fairly high percentage of cases of ACC, after selection for PD-1 (and possibly CTLA-4) expression, in association with microsatellite instability screening, a more frequent finding in ACC than previously recognized (7). Since immunotherapy is reserved to patients in advanced stages who have often been heavily treated, one open question remains if and how previous therapies can modify the expres- sion of checkpoint inhibitor molecules. The present study could not address this important point because most patients studied had localized tumors that did not require systemic treatment.
In addition to relieving immune inhibition by immunother- apy, a critical point to boost the antitumor immune response would consist of counteracting the immunosuppressive action of glucocorticoids in patients with tumors producing high levels of those steroids. Clinical studies are underway using different pharmacological treatments to assess the safety and efficacy of glucocorticoid suppression combined with immunotherapy in patients with advanced-stage ACC (NCT04373265, NCT05634577). Another strategy to improve the immune re- sponse against the tumor is to associate immunotherapy with anticancer vaccines: encouraging preliminary results have been reported for 1 ongoing clinical trial of this type in ACC (8). It is easy to predict that in the upcoming years more weapons will be available to clinicians to fight metastatic ACC by
harnessing the power of the immune response, which will hope- fully lead to better results than the current therapies.
Disclosures
The author has nothing to disclose.
References
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