Basics Of Immunology Ppt

[Peppin Kishore]

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The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.

The 1960s represented a period of enlightenment within the field of immunology because two major subtypes of lymphocytes, B lymphocytes and T lymphocytes, were characterized264,265. This was recognized by the 2019 Lasker Award for Basic Science, awarded for the pioneering work by Jacques A. F. P. Miller and Max Dale Cooper that defined the key roles of T cells and B cells in adaptive immunity. B cells recognize circulating antigen in its native form and respond by secreting protective antibodies266. By contrast, T cells recognize peptide antigens, derived from proteins degraded intracellularly, that are loaded onto cell surface MHC molecules, a process called antigen presentation. Two broad classes of T cells that have distinct effector mechanisms are delineated by the expression of either the CD4 or CD8 co-receptor: CD4+ T cells detect antigen in the context of MHC class II molecules and orchestrate the adaptive arm of the immune system by producing cytokines with chemotactic, pro-inflammatory and immunoprotective properties267. At least one CD4+ T cell subclass, CD4+CD25+ regulatory T cells, dampens the immune response following challenge268. CD8+ T cells detect antigen in the context of MHC class I molecules and carry out direct cytotoxic reactions that kill infected or neoplastic cells269.

Following activation, circulating naive T cells have three major fates in the periphery (Fig. 1). First, the effector T cell population can contract through apoptosis as the immune response resolves (cytokine withdrawal) or following repeated high-dose stimulation (restimulation-induced cell death)287,288,289. T cells can also exhibit an exhausted phenotype induced by repeated low-dose and low-affinity stimulation, as seen in chronic infections and neoplastic processes88. Lastly, a subset of these effector cells are involved in long-term immunological memory. Memory T cells are primed to react more vigorously to the same antigen during a subsequent encounter, making them critical mediators of immune recall responses to pathogens and tumours290. Leveraging the power of technological advances in molecular biology, recent single-cell RNA sequencing and epigenomic studies have provided additional molecular insight into T cell fates and the corresponding features of immunotherapy-responsive T cells. These studies collectively implicate that complex transcriptomic, epigenomic and clonotypic changes of tumour-infiltrating T cells determine the success of immunotherapy291,292,293,294.

After the discovery of T cell co-stimulation mediated by the surface protein CD28 (Box 1), the search for additional immune regulators led to the identification of CTLA4, a receptor with structural and biochemical similarities to CD28, as a new immunoglobulin superfamily member9,10. The CTLA4 and CD28 genes are found in the same region of chromosome 2 (2q33.2) and are selectively expressed in the haematopoietic compartment11. However, in contrast to the high levels of basal CD28 expression on conventional T cells, CTLA4 is expressed at a low basal level and is strongly induced following antigen activation. Interestingly, CD4+CD25+ regulatory T (Treg) cells, which have an immunosuppressive function, express CTLA4 constitutively. Structurally, both CTLA4 and CD28 form membrane-bound homodimers comprising an extracellular immunoglobulin-like domain, a transmembrane region and a cytoplasmic tail capable of recruiting signalling proteins and controlling surface expression10,12,13. The trafficking of CTLA4-containing vesicles to the cell surface after activation is controlled by a physical interaction with the lipopolysaccharide-responsive and beige-like anchor protein (LRBA)13. The sequence similarity between CTLA4 and CD28 is highest within their extracellular binding domain and they therefore bind to the same ligands, called B7-1 (also known as CD80) and B7-2 (also known as CD86), which are expressed by antigen-presenting cells (APCs; Box 1). However, CTLA4 has greater affinity and avidity than CD28 for B7 ligands, representing a key difference in their biology14,15,16.

Before activation, antigen-presenting cells (APCs) load antigen onto MHC molecules to prepare for contact with a T cell that displays a cognate T cell receptor (TCR) while also providing necessary co-stimulatory ligands B7-1 and B7-2. The inhibitory molecule cytotoxic T lymphocyte antigen 4 (CTLA4) is contained within intracellular vesicles in naive T cells, whereas it is constitutively expressed on the cell surface of CD4+CD25+ regulatory T (Treg) cells. Both classes of T cells express the co-stimulatory receptor CD28. Early after activation, generally in the lymphoid tissue, T cells are activated when their TCRs bind to their cognate antigen presented by APCs in conjunction with CD28 binding to B7-1/B7-2. Also, the activated T cells begin the process of displaying CTLA4 on the cell surface. T cells within peripheral tissues upregulate PD1 at the mRNA level early after activation. Late after activation, in lymphoid tissue, CTLA4 expressed by activated T cells binds to the B7-1 and B7-2 molecules on APCs, thereby preventing their binding to CD28 and promoting anergy by decreasing the T cell activation state. At the same time, constitutive expression of CTLA4 on Treg cells leads to trans-endocytosis of B7 ligands and interferes with the CD28 co-stimulatory ability of APCs. Late after activation in peripheral tissues, PD1 is further upregulated transcriptionally, leading to greater surface expression of programmed cell death 1 (PD1), which binds to its ligands PDL1 and PDL2, thereby promoting T cell exhaustion at sites of infection or when confronted with neoplasms. Image courtesy of the National Institute of Allergy and Infectious Diseases.

The recognition of CTLA4 as a negative regulator of T cell activation gave rise to the idea that blocking its actions could unleash a therapeutic response of T cells against cancer45 (Fig. 3). James Allison and colleagues first tested this idea and demonstrated that neutralizing anti-CTLA4 antibodies enhanced antitumoural immunity in mice against transplanted and established colon carcinoma and fibrosarcoma46. In addition, during rechallenge, animals treated with anti-CTLA4 were able to rapidly eliminate tumour cells through immune mechanisms, providing evidence that blocking of CTLA4 induces long-lasting immunological memory46,47. Although CTLA4-targeted monotherapy was shown to confer benefit in animal models of brain48, ovarian49, bladder50, colon46, prostate47 and soft tissue46 cancers, less immunogenic cancers, including SM1 mammary carcinoma51 and B16 melanoma52, did not respond as favourably. Furthermore, heterogeneity between cancer models yielded discordant tissue-specific results45,53. In addition, a greater tumour burden correlated with reduced tumour responses to anti-CTLA4 treatment because larger tumours foster a more robust anti-inflammatory tumour microenvironment45,49.

Cytotoxic T lymphocyte antigen 4 (CTLA4)-blocking antibodies (α-CTLA4), especially when bound to an Fc receptor (FcR) on an antigen-presenting cell (APC), can promote antibody-dependent cellular cytotoxicity (ADCC). CD4+CD25+ regulatory T (Treg) cells express higher amounts of CTLA4 than conventional T cells and are therefore more prone to α-CTLA4-induced ADCC than conventional T cells. In addition, α-CTLA4 can bind to CTLA4 on the surface of the Treg cell and prevent it from counter-regulating the CD28-mediated co-stimulatory pathways that are playing a role in T cell activation. At the same time, α-CTLA4 can also promote T cell responses by blocking CTLA4 on the surface of conventional T cells as they undergo activation. TCR, T cell receptor. Adapted from 2019 Fritz, J. M. & Lenardo, M. J. Originally published in J. Exp. Med. (ref.135).

Despite the mixed success in preclinical studies, mAbs targeting CTLA4 proved effective in clinical trials of melanoma45. Ipilimumab, a human IgG1κ anti-CTLA4 mAb, gained FDA approval in 2011 for non-resectable stage III/IV melanoma following evidence that it elicited potent tumour necrosis54 and conferred a 3.6-month short-term survival benefit55. Long-term survival data demonstrated that 22% of patients with advanced melanoma treated with ipilimumab benefited from an additional 3 years or more of life56. Additional long-term studies have demonstrated the durability of this survival benefit, indicating the persistence of antitumoural immunity following CTLA4 blockade56,57. Unfortunately, trial results in renal cell carcinoma58, non-small-cell lung cancer59, small-cell lung cancer60 and prostate cancer61 have yielded less impressive effects than those seen in patients with melanoma. Tremelimumab, an IgG2 isotype form of a CTLA4-blocking antibody, has yet to receive FDA approval as it did not increase survival in advanced melanoma62. It is hypothesized that effectiveness varies between ipilimumab and tremelimumab owing to differences in binding kinetics and the capacity to mediate antibody-dependent cell-mediated cytotoxicity63,64.

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