## 1 Introduction
To date, there are eight FDA approved mAbs that are used on a daily clinical routine, blocking PD-1 (nivolumab, pembrolizumab, cemiplimab, and dostarilmab), its ligand PD-L1 (atezolizumab, avelumab, and durvalumab) or the CTLA-4 receptor (ipilimumab), improving overall survival (OS) and progression-free survival (PFS) rates in a lot of patients with advanced malignancies, included melanoma, non-small-cell lung cancer (NSCLC), head and neck squamous cell carcinoma, urothelial carcinoma (UC), renal cell carcinoma (RCC), hepatocellular carcinoma, metastatic small-cell lung cancer (SCLC), colorectal carcinoma, and Hodgkin's lymphoma [8; 11; 19; 20; 21; 22], whereas alternative potential checkpoint targets in immune cells are under investigation, such as lymphocyte activation gene-3 (LAG-3) that interacts with major histocompatibility complex (MHC) class II, alongwith T cell immunoglobulin-3 (TIM-3) that binds with galectin-9 and carcinoembryonic antigen-related cell adhesion molecule (CARCAM)-1, preventing the promotion of immune tolerance [21]  
Despite the promising results of immunotherapy, several patients will not benefit from this therapy. Many tumor cells' intrinsic and extrinsic factors induce primary resistance mechanisms, including insufficient tumor immunogenicity and neoantigen presentation (MHC dysfunction), PD-L1 expression and irreversible T cell exhaustion, immunosuppressive tumor microenvironment (TME), and cellular signaling pathways as a primary resistance to INF-\(\gamma\) signaling [14; 23]. Hence, predictive biomarkers that determine tumor response to therapy are essential. It is debated, though, whether the PD-L1 tumor microenvironment overexpression is a positive or negative biomarker. High nonsynonymous mutation burden, DNA mismatch repair deficiency, and tumor-infiltrating immune cells are also possible predictive factors; however, their use is limited [5; 10; 24]. Nevertheless, the host's immune system and gut microbiome are critical parameters in the prediction of the response in any type of therapy. Peripheral blood biomarkers such as absolute neutrophil count, neutrophil to lymphocytes ratio, eosinophil counts and lactate dehydrogenase levels may anticipate cheaper and more accessible predictive markers [5; 10; 24; 25; 26]. ICIs are considered to have less toxicity and better safety and tolerance in comparison to conventional treatment, though, occasionally, toxicity can range from mild to fatal, inducing the discontinuation of immunotherapy [27; 28]. Most toxicities are the result of excessive immune activation against healthy tissues and could affect any organ system [29]. These immune-related adverse events (irAEs) have a median onset within 2-16 weeks from the first dose of immunotherapy; nevertheless, late irAEs could be mentioned even after 12 months from the completion of therapy [29; 30]. The severity of irAEs depends on the used ICI, the dose, and the host's immune status, and increases exponentially by receiving a combination of agents [28; 29]. Conventionally, irAEs are endocrinopathies, cutaneous, gastrointestinal, pulmonary, renal, neurologic, rheumatic manifestations, and vasculitis; however, autoimmune colitis, pneumonitis, and myocarditis are the most fatal [28; 29; 30; 31; 32; 33; 34; 35]. Although there is a strong correlation between irAEs and improved PFS in patients who received ICIs, there is a need to develop personalized surveillance strategies during treatment to reduce the incidence and mortality of immune-related toxicities [28; 36]. As far as B cells are concerned, their role in cancer immunity is controversial [37; 38]. Studies report that they can have both protumor and antitumor effects and their activity depends on various factors, including the context of the tumor microenvironment, the histologic type of cancer, and the stage of cancer progression. Beyond any doubt, their involvement in adaptive immunity as antibody-secreting cells (ASCs), antigen-presenting cells (APCs), and cytotoxic cells is well clarified [37; 39].