Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire

Abstract

While immune checkpoint blockade elicits efficacious responses in many cancer patients, it also produces a diverse and unpredictable number of immune-related adverse events (IRAE). Mechanisms driving IRAE are generally unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined in this study whether ipilimumab treatment leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T cell repertoire to a limited number of clones, ipilimumab induced greater diversification in the T cell repertoire in IRAE patients compared to patients without IRAE. Specifically, ipiliumumab triggered increases in the numbers of clonotypes, including newly detected clones and a decline in overall T cell clonality. Initial broadening in the repertoire occurred within 2 weeks of treatment, preceding IRAE onset. IRAE patients exhibited greater diversity of CD4+ and CD8+ T cells, but showed no differences in regulatory T cell numbers relative to patients without IRAE. PSA responses to ipilimumab were also associated with increased T cell diversity. Our results show how rapid diversification in the immune repertoire immediately after checkpoint blockade can be both detrimental and beneficial for cancer patients.

iReceptor: A platform for querying and analyzing antibody/B‐cell and T‐cell receptor repertoire data across federated repositories

“…They showed that the number of expanded clones (leading to lower diversity) in the CD8 T-cell repertoire strongly correlated with the probability of suffering adverse effects. Unfortunately, these results are nearly the opposite of those of Oh et al 25 who also studied metastatic prostate cancer patients treated with ipilimumab.…”

The T cell repertoire in tumors overlaps with pulmonary inflammatory lesions in patients treated with checkpoint inhibitors

“…Recent studies have also shown an expansion of autoreactive T cell clones in the periphery upon treatment with CTLA-4 blocking antibodies in patients with prostate cancer. 20 Not only an expansion of clones was seen but also a diversification of T cells was detected in prostate cancer patients treated with CTLA-4 blocking antibodies and experiencing irAEs 21 , which supports the hypothesis that newly developed reactivity to shared auto-antigens may play role in the generation of inflammatory complications in patients undergoing checkpoint blockade. An important question with regard to shared antigens is if identified frequent clones that are most likely tumor-reactive are causative for irAE lesions or inflammation in target organs of irAEs driven by other T cell clones attracts tumor specific T cells into these organs as a non-specific secondary event.…”

“…25 Treatment with checkpoint inhibitors including CTLA-4 blocking antibodies can induce epitope spreading. 21,22,26 Epitope spreading could enhance anti-tumor responses but also the generation of inflammatory complications of checkpoint blockade. Epigenetic reprogramming of T cells is also possibly involved in a break of peripheral tolerance towards autoantigens and could support the development of irAEs.…”

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…In agreement with this, treatment with ipilimumab was found to broaden the TCR repertoire more robustly, within 2 weeks, in those experiencing irAEs than in those without irAEs, and treatment response improved along with the increase in TCR diversity. This further underscores cancer immunotherapy as a double-edged sword in which patients and clinicians must weigh the risk of immunotoxicity against the benefit of tumor destruction 35 . By comparison, PD-1 blockade is likely to reinvigorate a previously overactive immune system 32 ; studies of T cell exhaustion in chronic infection show that PD-1 functions to limit effector T cell-mediated inflammatory injury 36 .…”