Ashi Mohamad Omar, Mami-Chouaib Fathia, Corgnac Stéphanie
INSERM UMR 1186, Integrative Tumor Immunology and Immunotherapy, Gustave Roussy, Fac. de Médecine - Univ. Paris-Sud, Université Paris-Saclay, 94805 Villejuif, France.
Explor Target Antitumor Ther. 2022;3(6):746-762. doi: 10.37349/etat.2022.00111. Epub 2022 Dec 22.
Major advances in cancer treatment have emerged with the introduction of immunotherapies using blocking antibodies that target T-cell inhibitory receptors, such as programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), known as immune checkpoints. However, most cancer patients do not respond to immune checkpoint blockade (ICB) therapies, suggesting the development of resistance mechanisms associated with either an insufficient number of preexisting tumor-specific T-cell precursors and/or inappropriate T-cell reactivation. To broaden clinical benefit, anti-PD-1/PD-1 ligand (PD-L1) neutralizing antibodies have been combined with therapeutic cancer vaccines based on non-mutant and/or mutant tumor antigens, to stimulate and expand tumor-specific T lymphocytes. Although these combination treatments achieve the expected goal in some patients, relapse linked to alterations in antigen presentation machinery (APM) of cancer cells often occurs leading to tumor escape from CD8 T-cell immunity. Remarkably, an alternative antigenic peptide repertoire, referred to as T-cell epitopes associated with impaired peptide processing (TEIPP), arises on these malignant cells with altered APM. TEIPP are derived from ubiquitous non-mutant self-proteins and represent a unique resource to target immune-edited tumors that have acquired resistance to cytotoxic T lymphocytes (CTLs) related to defects in transporter associated with antigen processing (TAP) and possibly also to ICB. The present review discusses tumor-associated antigens (TAAs) and mutant neoantigens and their use as targets in peptide- and RNA-based therapeutic cancer vaccines. Finally, this paper highlights TEIPP as a promising immunogenic non-mutant neoantigen candidates for active cancer immunotherapy and combination with TAA and mutant neoantigens. Combining these polyepitope cancer vaccines with ICB would broaden T-cell specificity and reinvigorate exhausted antitumor CTL, resulting in the eradication of all types of neoplastic cells, including immune-escaped subtypes.
随着使用靶向T细胞抑制受体（如程序性死亡-1（PD-1）和细胞毒性T淋巴细胞相关抗原4（CTLA-4），即免疫检查点）的阻断抗体的免疫疗法的引入，癌症治疗取得了重大进展。然而，大多数癌症患者对免疫检查点阻断（ICB）疗法没有反应，这表明存在与预先存在的肿瘤特异性T细胞前体数量不足和/或不适当的T细胞重新激活相关的耐药机制。为了扩大临床益处，抗PD-1/PD-1配体（PD-L1）中和抗体已与基于非突变和/或突变肿瘤抗原的治疗性癌症疫苗联合使用，以刺激和扩增肿瘤特异性T淋巴细胞。尽管这些联合治疗在一些患者中达到了预期目标，但与癌细胞抗原呈递机制（APM）改变相关的复发经常发生，导致肿瘤逃避CD8 T细胞免疫。值得注意的是，在这些APM改变的恶性细胞上出现了一种替代抗原肽库，称为与肽加工受损相关的T细胞表位（TEIPP）。TEIPP源自普遍存在的非突变自身蛋白，是靶向对与抗原加工相关的转运体（TAP）缺陷以及可能对ICB产生耐药性的免疫编辑肿瘤的独特资源。本综述讨论了肿瘤相关抗原（TAA）和突变新抗原及其在基于肽和RNA的治疗性癌症疫苗中的应用。最后，本文强调TEIPP作为活性癌症免疫治疗以及与TAA和突变新抗原联合使用的有前景的免疫原性非突变新抗原候选物。将这些多表位癌症疫苗与ICB联合使用将拓宽T细胞特异性并重振耗竭的抗肿瘤CTL，从而根除所有类型的肿瘤细胞，包括免疫逃逸亚型。
