Critical Roles of Chemoresistant Effector and Regulatory T Cells in Antitumor Immunity after Lymphodepleting Chemotherapy

Abstract

Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8+ T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4+CD25+ Foxp3+ Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4+ T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8+ T cells were responsible for this augmentation. Using Rag2−/− mice or depletion of recipient CD8+ T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4+ T cells enhanced the proliferation of CD8+ T cells and the priming of tumor-specific CD8+ T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies.

Successful Transfer of Umbilical Cord Blood CD34+ Hematopoietic Stem and Progenitor-derived NK Cells in Older Acute Myeloid Leukemia Patients

“…This study design allowed us to separate toxicity induced by cyclophosphamide and fludarabine conditioning and HSPC-NK cell infusion from IL2-mediated toxicity, which can be considerable (31). Besides, it has been reported that Tregs, capable of suppressing NK-cell function, are relative resistant to cytotoxic therapy and expand rapidly after IL2 administration (23,25,32,33). Although we did observe a relative increase in Tregs at day 14 after HSPC-NK cell infusion, the absolute Treg number before and after treatment was unchanged.…”

Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights

“…However, the identification of neoantigens depends on targeting “driver” mutations first, and many questions remain unanswered regarding how to precisely define and distinguish between “driver” mutations or clinically actionable mutations (responsive to targeted therapies) from the much larger set of passenger alterations embedded in tumor DNA . The emerging concept of non‐coding drivers adds additional challenges to precisely define or identify “neoantigens.” In addition, the use of host lymphodepletion‐chemotherapy with immunosuppressive agents (e.g., cyclophosphamide) is required to augment the antitumor effects of CART . Unfortunately, these concomitant therapies can lead to clinical cardiotoxicity …”

“…In addition, the use of host lymphodepletion-chemotherapy with immunosuppressive agents (e.g., cyclophosphamide) is required to augment the antitumor effects of CART. 584 Unfortunately, these concomitant therapies can lead to clinical cardiotoxicity. [585][586][587][588] The recent experiences with severe, life-threatening episodes of cardiotoxicity associated with ICIs and CART gives rise to some important concerns that are biologically and clinically relevant for future preclinical studies, oncology trials, and clinical practice to limit the uncontrolled activation of immune responses.…”

Potato freeze‑thaw solution enhances immune function and antitumor activity in?vivo

“…To suppress the immune function of mice, all mice were injected intramuscularly with cyclophosphamide (4 mg) 1 and 3 days prior to further treatment (16). In total, 20 mice were then each administered either 1 ml of PFTS or 1.8 mg of Ganoderma lucidum (G. lucidum; Research Center of Bioresource & Bioenergy, School of Biotechnology, Jiangnan University, Jiangsu, China) twice a day by gavage.…”