Inmunoterapia en cáncer: Perspectivas actuales, desafíos y nuevos horizontes / Immunotherapy in cancer. Current prospects, challenges and new horizons

La activación del sistema inmunológico en pacientes con cáncer ha sido un objetivo histórico en el campo de la oncología. En las últimas décadas, nuestro entendimiento de la respuesta inmunológica antitumoral ha promovido el desarrollo de novedosas estrategias terapéuticas dando como resultado un cambio de paradigma en el tratamiento del cáncer. La utilización de agentes bloqueantes de puntos de chequeo del sistema inmunológico como PD-1/PD-L1 y CTLA-4, de agonistas de moléculas co-estimuladoras como CD137 y OX-40 y la transferencia adoptiva de células T antitumorales modificadas genéticamente han generado importantes beneficios clínicos, reflejados en respuestas objetivas y durader as, en enfermos sin tratamientos convencionales disponibles. Sin embargo, un gran número de pacientes no responde a dichas terapias generando resistencia o sufriendo recaídas de la enfermedad debido a la aparición de circuitos inhibitorios o compensatorios. La combinación racional de estrategias terapéuticas permite eliminar mecanismos de resistencia, mientras que la identificación de biomarcadores predictivos facilita la selección de pacientes respondedores a dichos tratamientos. Recientes ensayos clínicos y estudios pre-clínicos permiten vislumbrar un escenario optimista con importantes desafíos en la implementación de estrategias de inmunoterapia en cáncer.

Recent under-standing of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits. Rational combination of immunotherapeutic modalities will help overcome resistance and will increase the number of patients who will benefit from these treatments. Moreover, identification of predictive biomarkers will allow selection of patients responding to these treatments. Emerging clinical trials and pre-clinical studies have shown exciting results anticipating new horizons in the design and implementation of cancer immunotherapeutic modalities.

Effects of lupeol on human co-stimulation cells and colonic cancer cell lines SW480 / 医学研究生学报

Objective Co-stimulation cells is a kind of natual killer (NK)-like T cells, which can kill tumor cells.Previous studies show that lupeol , an natural plant extracts , can change the growth of NK cells ,γδT cells and their effects on tumor cells .This study aimed to investigate the effects of lupeol on human co-stimulation cells and colonic cancer cell lines SW 480 . Methods The peripheral blood mononuclear cells ( PBMC) from healthy volunteers were induced in vitro by different cytokines and transferred into Co-simulation cells.After SW480 and Co-stimulation cells were incubated with different concentrations of lupeol for different durations , methyl thiazolyl tetrazolium (MTT) was used to detect the effects of lupeol on co-stimulation cells and colonic cancer cell lines SW480. Lactate dehydrogenase was used to determine the cell-killing activity of Co-simulation cells to colonic cancer lines SW 480 . Results The concentration of lupeol in 0.1-200.0 mg/L promoted the growth of Co-stimulation cells and inhibited the colonic cancer cell lines SW480.When the concentration of lupeol is at 12.5 mg/L, the cell-killing activity of Co-simulation cells to colonic cancer lines SW 480 was enhanced significantly compared with the controls (76%vs 40%, P<0.05). Conclusion Lupeol could promote the prolifera-tion of Co-stimulation cells, inhibit the growth of cancer lines SW480, and strengthen the cytotoxicity of Co-stimulation cells against co-lonic cell lines SW480.

The CD28-B7 Family in Anti-Tumor Immunity: Emerging Concepts in Cancer Immunotherapy

The interactions between B7 molecules and CD28-family receptors are crucial in the regulation of adaptive cellular immunity. In cancer, the aberrant expression of co-inhibitory B7 molecules has been attributed to reduced anti-tumor immunity and cancer immune evasion, prompting the development of cancer therapeutics that can restore T cell function. Murine tumor models have provided significant support for the targeting of multiple immune checkpoints involving CTLA-4, PD-1, ICOS, B7-H3 and B7-H4 during tumor growth, and clinical studies investigating the therapeutic effects of CTLA-4 and PD-1 blockade have shown exceptionally promising results in patients with advanced melanoma and other cancers. The expression pattern of co-inhibitory B7 ligands in the tumor microenvironment has also been largely correlated with poor patient prognosis, and recent evidence suggests that the presence of several B7 molecules may predict the responsiveness of immunotherapies that rely on pre-existing tumor-associated immune responses. While monotherapies blocking T cell co-inhibition have beneficial effects in reducing tumor burden, combinatorial immunotherapy targeting multiple immune checkpoints involved in various stages of the anti-tumor response has led to the most substantial impact on tumor reduction. In this review, we will examine the contributions of B7- and CD28-family members in the context of cancer development, and discuss the implications of current human findings in cancer immunotherapy.

Emerging Co-signaling Networks in T Cell Immune Regulation

Co-signaling molecules are surface glycoproteins that positively or negatively regulate the T cell response to antigen. Co-signaling ligands and receptors crosstalk between the surfaces of antigen-presenting cells (APCs) and T cells, and modulate the ultimate magnitude and quality of T cell receptor (TCR) signaling. In the past 10 years, the field of co-signaling research has been advanced by the understanding of underlying mechanisms of the immune modulation led by newly identified co-signaling molecules and the successful preclinical and clinical trials targeting co-inhibitory molecules called immune checkpoints in the treatment of autoimmune diseases and cancers. In this review, we briefly describe the characteristics of well-known B7 co-signaling family members regarding the expression, functions and therapeutic implications and to introduce newly identified B7 members such as B7-H5, B7-H6, and B7-H7.

Expression and Function of TLR2 on CD4 Versus CD8 T Cells

BACKGROUND: Toll-like receptors (TLRs) play a fundamental role in innate immunity through their capacity to recognize pathogen-associated molecular patterns. Also, TLRs that are expressed in T cells are reported to function as co-stimulatory receptors. However, the functional capacity of TLRs on CD4 T and CD8 T cells has not been directly compared. Here we compared CD4 and CD8 T cell responses to TLR2 ligand plus TCR-mediated stimulation. METHODS: TLR2 expression was analyzed on T cell subsets under naive and alloantigen-primed conditions. We analyzed the effects of TLR2 co-stimulation on proliferation and survival of T cell subsets in vitro when stimulated with soluble anti-CD3 in the presence or absence of synthetic ligand Pam3CSK4. RESULTS: TLR2 expression on CD8 T cells was induced following activation; this expression was much higher than on CD4 T cells. Thus, the molecule was constitutively expressed on Listeria-specific memory CD8 T cells. Based on these expression levels, proliferation and survival were markedly elevated in CD8 T cells in response to the TLR2 co-stimulation by Pam3CSK4 compared with those in CD4 T cells. CONCLUSION: Our data show that TLR2 co-stimulation is more responsible for proliferation and survival of CD8 T cells than for that of CD4 T cells.

The Differential Effects of Donor-Strain Immature Dendritic Cell Subtypes and the Blockade of CD40/CD154 Pathway on the Creation of Allograft Tolerance / 대한신장학회잡지

BACKGOUND: Dendritic cells (DC) are pivotal antigen presenting cells and serve a unique role in initiating immunity. To test the hypothesis that pre-immunization of recipient with certain DC subsets of donor origin can influence graft outcome. METHODS: We have studied the effects of immunization with allogeneic CD4+CD11c+(MDC) and CD8+CD11c+(LDC) DCs on the allograft response. RESULTS: Both immature MDC and LDC subsets from DBA/2 were able to prime naive allogeneic C57BL/6 (B6) T cells in MLR. In vitro allogeneic T cell responses were attenuated by the addition of anti-CD154 mAb into the culture. T cells from B6 mice that received DBA/2 MDC intravenously 4 weeks before testing mounted weaker MLR driven cell proliferation than T cells from LDC pretreated B6 mice. Consistent with the MLR results, combined pretreatment with MDC, but not LDC, plus anti-CD154 mAb produced donor-strain specific long-term graft survival and induced tolerance while treatment with LDC plus anti-CD154 mAb created minimal prolongation of allograft survival in a pancreas islet transplant model (DBA/2->B6). The beneficial effects exerted by MDC and anti-CD154 mAb pretreatment were correlated with TH1 to TH2 immune deviation and with the amplified donor-specific suppressive capacity by recipient CD4+CD25+T cells. CONCLUSION: These findings highlight the capacity of MDC to modulate alloimmune responses, and suggest therapeutic approaches for the induction of donor specific tolerance.

ADVANCES IN RESEARCH OF TRANSPLANTATION TROLERACE / 解放军医学杂志

Recent advances in transplantation tolerance were comprehensively reviewed. The contents included the mechanisms and methods of induction and maintenance of transplantation tolerance. Some experimental protocols were introduced including mixed chimerism of allogeneic bone marrow, blockade of co-stimulation signal and transgene technology for transplantation tolerance induction. The problems and the future of clinical transplantation tolerance were objectively evaluated here.