Question

We learned about PD-1 and CTLA4 under the topic - costimulation. Feel free to revisit that topic. Now explain (with precise cellular and molecular processes related words) that how anti-PD1 and anti-CTLA4 antibodies are likely to treat cancer.

"In the 1890s, oncologist William Coley began to inject cancer patients who had inoperable tumors with a mixture of killed bacteria. Coley reported success with the approach and “Coley’s toxins” were sold as a cancer therapy in the United States even into the 1960s." This concept became the premise for one of the approaches in modern day immunotherapy. What is the concept underlying Coley's experiments?

Answer 1

Anti-PD1 and anti-CTLA4 enhance antitumour activity through reduction of intratumoral regulatory T cells. During chronic inflammation in particular ,T cells are known to be exhausted and to upregulate wide range of non redundant inhibitory receptors that limit their effectiveness, such as PD1,CTLA4 ,Tcell immunoglobin etc.Here when host fail to clear pathogen ,exhaust cells can cause cancer.Under these conditions,perisistent high antigenic load cells to the T cells upregulating the inhibitory receptors,whose signalling subsequently lead to progressive loss of proliferative potential and effector functions and in some cases lead to their deletion.

The main concept in coley's experiment is that the innate immune system must be harnessed robustly to fully activate tumour specific T cells ,  a positive corelation between spontaneous regression and febrile infection ,epidemiological data suggesting an inverse correlation between a history of infection and liklihood of developing cancer ,a complex mixture of gram positive and gram negetive bacterial compounds ,as an active antineoplastic agent .Rapidly growing tumours contain large no of leaucocyts .These cells play part in both defence and repair.However repetative functions can cause tumours .Intratumoural infections may reactivate defensive functions,causing tumour regression.