Targeting Immune Regulatory Networks to Counteract Immune Suppression in Cancer

Abstract

The onset of cancer is unavoidably accompanied by suppression of antitumor immunity. This occurs through mechanisms ranging from the progressive accumulation of regulatory immune cells associated with chronic immune stimulation and inflammation, to the expression of immunosuppressive molecules. Some of them are being successfully exploited as therapeutic targets, with impressive clinical results achieved in patients, as in the case of immune checkpoint inhibitors. To limit immune attack, tumor cells exploit specific pathways to render the tumor microenvironment hostile for antitumor effector cells. Local acidification might, in fact, anergize activated T cells and facilitate the accumulation of immune suppressive cells. Moreover, the release of extracellular vesicles by tumor cells can condition distant immune sites contributing to the onset of systemic immune suppression. Understanding which mechanisms may be prevalent in specific cancers or disease stages, and identifying possible strategies to counterbalance would majorly contribute to improving clinical efficacy of cancer immunotherapy. Here, we intend to highlight these mechanisms, how they could be targeted and the tools that might be available in the near future to achieve this goal.

Transfer of in vitro-expanded naïve T cells after lymphodepletion enhances antitumor immunity through the induction of polyclonal antitumor effector T cells

“…Moreover, the depletion of host Tregs that are resistant to lymphodepletion results in the successful treatment of advanced tumor models when combined with lymphodepletion by cyclophosphamide and the transfer of naïve T cells [ 4 ]. Extensive studies have revealed that tumors induce immune suppression to evade antitumor T cell responses [ 13 – 15 ]. Several mechanisms have been suggested for the induction of immune suppression by tumors, including induction of Tregs, myeloid-derived suppressor cells, tumor-associated macrophages and tolerogenic DCs; secretion of immunosuppressive soluble factors; and activation of negative regulatory pathways such as CTLA-4 and PD-1.…”

“…However, TCR functions are impaired in tumor-bearing hosts [ 11 ] [ 12 ]. Tumor cells induce immunosuppressive mechanisms, such as the induction of regulatory cell populations and the secretion of immunosuppressive soluble factors, and they also inhibit the function of antitumor T cells [ 13 , 14 ] [ 15 ]. Thus, it remains difficult to harvest a sufficient number of fully functional naïve T cells from cancer patients.…”

A Modern View on the Problem of Treatment of Urothelial Cancer

“…Залогом успешной терапии является понимание процессов, происходящих в опухолевом микроокружении, одним из определяющих факторов которого является уровень инфильтрации опухоли Т-клетками. Оценить Т-клеточную инфильтрацию возможно, исследовав уровень T-регуляторных лимфоцитов (Т-reg), а также связанных с опухолью макрофагов, сосудистых эндотелиальных клеток, фибробластов и иммуносупрессивных метаболитов, например кинуренина [61].…”

“…Изучение Т-reg, которые являются одним из сильнейших иммуносупрессоров микроокружения, проводили с помощью МКАт и дендритноклеточных (ДК) вакцин. Клинические иссле-Черные -в разработке Красные -утверждены дования даклизумаба, сорафениба (ингибитора тирозинкиназ), сунитиниба и иматиниба показали снижение количества T-reg (при раке простаты, колореклальном раке), что коррелировало с общей выживаемостью [61]. Данные исследования представляются перспективными в отношении УР.…”

Modern pharmacotherapy in the fight against multidrug resistance in cancers

“…Pierwsze próby wdrożenia tej metody polegały na nieswoistej stymulacji układu immunologicznego przez adiuwanty odpowiedzi immunologicznej oraz cytokiny (takie jak np. interleukina 2, interferon-alfa, czynnik martwicy guza alfa), dopiero później zaczęto wykorzystywać swoiste antygeny nowotworowe lub ich syntetyczne odpowiedniki, które miały stymulować endogenną odpowiedź obronną, głównie na drodze pobudzenia cytotoksycznych limfocytów T [30]. Preparaty zawierające te substancje są najczęściej podawane miejscowo, jako szczepionki doguzowe.…”