RCC Immune Microenvironment Subsequent to Targeted Therapy: A Friend or a Foe?

Abstract

Renal cell carcinoma (RCC) is composed of different subtypes with distinct molecular and histological tumor heterogeneity. Although the advent of various targeted therapies has improved the survival of patients with advanced RCC over the past 15 years (since 2006), few cases experienced complete response due to drug resistance. Recent studies have demonstrated that the outcomes following targeted therapies are potentially associated with intricate cross-links between immune responses and suppressors in the tumor microenvironment (TME). In addition, progress on drug research and development enhances our awareness and understanding about immunotherapy and combined treatment. In this review article, we intend to make a comprehensive summary about TME and its alterations following targeted therapies, provide valid evidence in this aspect, and discuss optimal matches between targeted therapy and immunotherapy.

Bioinformatic analysis identifying FGF1 gene as a new prognostic indicator in clear cell Renal Cell Carcinoma

“…Renal cell carcinoma has been a common malignant tumor of urinary tract, ranking only second to bladder carcinoma in morbidity of all adults urinary tract malignant tumors. Although the clinical treatment situation is still challenging given the tumor heterogeneity and evolutionary nature of cancer [ 32 , 33 ], the increasing developing molecular pathology has been bringing promising effect for ccRCC in both molecular diagnosis and targeting treatment. Especially in current precise medicine era, the various bioinformatic analysis tools has been making it more practicable for worldwide researchers to explore the molecular genetic abnormalities in cancers [ 34 , 35 ].…”

Bioinformatic Analysis Identifing FGF1 Gene as a New Prognostic Indicator in Clear Cell Renal Cell Carcinoma 

“…Renal cell carcinoma has been a common malignant tumor of urinary tract, ranking only second to bladder carcinoma in morbidity of all adults urinary tract malignant tumors, and within RCC, 65%~70% is clear cell renal cell carcinoma. Although the current molecular pathology has been rapidly developing and bringing promising effect for ccRCC in both molecular diagnosis and targeting treatment, the current situation is still challenging given the tumor heterogeneity and evolutionary nature of cancer [32,33].…”

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

“…A substantial subset of mRCC patients do not respond to ICIs, and patients who initially respond, eventually progress [62,123]. Accordingly, the most potential combination treatment should meet one of the following requirements: (a) ICIs plus immune TME-modifying and anti-angiogenic agents; (b) immune TME-modifying agents plus anti-angiogenic agents; and (c) adoptive T cell therapy plus anti-angiogenic agents [124]. Immunotherapy attenuates immunosuppression and decreases tumor vascularization, and anti-angiogenic drugs reduce the percentage of immunosuppressive cells, thus blocking immune escape.…”

“…Immunotherapy attenuates immunosuppression and decreases tumor vascularization, and anti-angiogenic drugs reduce the percentage of immunosuppressive cells, thus blocking immune escape. The dominant challenge is to identify an optimal combination of these two treatments and obtain the optimal dosage of combined therapy to magnify the clinical benefits [124]. The therapeutic potential of combinatorial approaches targeting checkpoint molecules alone or in combination with other checkpoint blockers, targeted therapies, or radiation have been extensively explored [16,52,53,[125][126][127].…”

“…Furthermore, angiogenic factors such as VEGF drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immunosuppressive activity of Treg, myeloid-derived suppressor cells (MDSCs), and TAMs [47,124,150]. DC immaturity occurs when VEGF binds to VEGF receptor 2 (VEGFR2), thus decreasing antigen presentation and increasing PD-L1 expression in DCs [124].…”